Articles de revues : « Epidermal Growth Factor Breast Neoplasms Breast Neoplasms »

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Degu, Amsalu, et Asha Yussuf. « Treatment outcomes among human epidermal growth factor receptor 2 positive breast cancer patients : A systematic review ». Journal of Oncology Pharmacy Practice 27, n^o 6 (31 mars 2021) : 1468–76. http://dx.doi.org/10.1177/10781552211005530.

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Background The incidence of human epidermal growth factor receptor 2 (HER 2) positive breast cancers is rapidly rising worldwide. Although there have been many studies on HER 2 breast cancer treatment and management in recent years, there is a lack of comprehensive reports on the treatment outcomes and disparities within the available literature. Hence, this review aimed to determine the treatment outcomes and their associated factors among patients with HER2-positive breast cancer. Methods A computer-based systematic literature search was conducted using PubMed, EMBASE, and Google scholar databases of articles published from 2000 to 2020. The following key terms (HER 2 positive breast cancer, predictor, determinant, associated factor) and Medical Subject Headings (MeSH) terms (breast neoplasms, treatment outcome, and risk factors) were used to search the English language published articles. Results In most studies, trastuzumab was the most commonly used treatment regimen used in combination with chemotherapeutic agents. Generally, most of the studies (15 studies) showed that the overall survival outcome was relatively higher after treatment among HER2 positive breast cancer patients. Nonetheless, two studies showed that the absence of significant change in the overall survival despite adequate treatment was given to the study participants. In addition, three studies demonstrated a partial response after treating HER2-positive breast cancer patients. Conclusion Generally, the overall survival outcome was relatively higher after treatment among HER2 positive breast cancer patients. The addition of trastuzumab in most of the studies has shown improvement in the overall survival and the disease-free survival rate of the study patients.

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Gomez, Henry L., Carlos Castañeda, Fernando Valencia, Rene Muñoz-Bermeo, Maria del Carmen Torrico et Silvia Neciosup. « ABC4 Consensus : First Latin American Meeting—Assessment, Comments, and Application of Its Recommendations ». JCO Global Oncology, n^o 6 (septembre 2020) : 819–27. http://dx.doi.org/10.1200/go.20.00081.

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Breast cancer accounts for a high burden among all the neoplasms in Latin America, with more-advanced stages at presentation, which could result in high mortality rates. The 4th International Consensus Conference for Advanced Breast Cancer (ABC4) is focused on standardizing therapy for advanced breast cancer (ABC) and has held 5 meetings so far. ABC4 took place in Lisbon, Portugal, from November 2 to 4, 2017; however, the first Latin American ABC conference was held in Lima, Peru, from 18 to 19 May, 2018, chaired by Fatima Cardoso, MD, PhD. During these 2 days, the ABC4 consensus recommendations for advanced and locally advanced breast cancer were presented. Local treatment and systemic therapy were discussed with local experts, mainly focusing on anti–human epidermal growth factor receptor 2 therapy and newly approved drugs for hormone receptor–positive breast cancer, such as as CDK4/6, mammalian target of rapamycin, and poly (ADP-ribose) polymerase inhibitors for triple-negative breast cancer. The discussion focused additionally on access to drugs and ABC4 consensus recommendations as regards Latin American patients.

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Prayogo, Ami Ashariati, Andi Yasmin Wijaya, Winona May Hendrata, Steven Sheng Looi, Reny I’tishom, Lukman Hakim, Fedik Abdul Rantam, I. Ketut Sudiana et Abdurachman Abdurachman. « Dedifferentiation of MCF-7 Breast Cancer Continuous Cell Line, Development of Breast Cancer Stem Cells (BCSCs) Enriched Culture and Biomarker Analysis ». Indonesian Biomedical Journal 12, n^o 2 (29 juin 2020) : 115–23. http://dx.doi.org/10.18585/inabj.v12i2.977.

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BACKGROUND: Cancer stem cells (CSCs) eradication might serve as a robust approach for cancer eradication. MCF-7 as breast cancer continuous cell line is known to contain breast CSCs (BCSCs) for its capability to maintain its original tumor population. CSCs enriched culture is a fundamental tool for CSCs targeted therapy development. Effective and unsophisticated CSCs dedifferentiation protocol for producing CSCs enriched culture is needed.METHODS: MCF-7 cells were cultured initially in Dulbecco's Modified Eagle Medium (DMEM) low glucose medium then changed to DMEM:F12. Serum starvation was performed during each medium refreshment gradually with fetal bovine serum (FBS) concentration of 10%, 5%, 2.5% until reaching 1% FBS concentration. Stable MCF-7 culture was then adapted to serum free culture system, containing DMEM:F12, epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), and B27 supplement as dedifferentiation protocol for 18 days. Cluster of differentiation (CD)44 and CD24 double staining immunocytochemistry was performed to evaluate cell stemness.RESULTS: The population of cells expressing BCSCs markers (CD44+/CD24low) in non-adherent single cells subpopulation was significantly increased after the dedifferentiation procedure (70.39%) compared to control groups (0.71%) (p<0.05). In contrast, the expression of BCSCs marker in adherent single cells subpopulation and for both adherent and non-adherent mammosphere the BCSCs markers showed a stable expression.CONCLUSION: BCSCs enrichment of breast cancer cell cultures from MCF-7 breast cancer cell line can be performed. Breast cancer cell plasticity is observed during the dedifferentiation protocol. Development of dedifferentiation inducing protocols can serve as an important foundation for breast cancer therapy development through BCSCs elimination.KEYWORDS: breast neoplasms, cell line, dedifferentiation, immunohistochemistry, neoplastic stem cells

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Oliveira, Iandra Freire, Jhonata Lima Rocha, Anamaria Falcão Pereira, Marina Helena Silva Lopes, Aurilene Gomes Cajado, Rosane Oliveira Sant'Ana, Paulo Roberto Carvalho Almeida, Roberto César Pereira Lima et Deysi Viviana Tenazoa Wong. « Association of cytoplasmic HMGB1 (cHMGB1) expression with local tumor recurrence in triple-negative breast cancer. » Journal of Clinical Oncology 39, n^o 15_suppl (20 mai 2021) : e12595-e12595. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e12595.

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e12595 Background: Breast cancer is one of the most frequent neoplasms worldwide, contributing to women's morbimortality. Triple-negative breast cancer (TNBC) is a highly aggressive subtype of cancer marked by negative estrogen receptors, progesterone receptors, and lack of the human epidermal growth factor 2 (C-erbB2, HER2/neu) gene overexpression. The high mobility group box-1 (HMGB1) is a factor that regulates malignant tumorigenesis, proliferation, and metastasis. Aim: Here, the HMGB1 expression was investigated as a prognostic factor for TNBC. Methods: Clinico-pathological data and surgical paraffin histopathology blocks were assessed from 85 patients treated at Haroldo Juaçaba Hospital (Ethics committee approval number 407.395). Samples were analyzed by immunofluorescence using the Tissue Microarray technique to determine the percentage of fluorescent cells with cytoplasmic HMGB1 (cHMGB1) expression. Results: The clinico-pathological data analysis indicated that patients were older than 50 years (68.2%) and diagnosed with grade 2–3 ductal carcinomas (91.8%). Tumor metastasis was observed in 9.9% of cases. TNBC patients that tumor cells presented high cHMGB1 fluorescence demonstrated increased local tumor recurrence compared with low expressing tumors (P=0.019). Five-year overall survival was simmilar between the patients with low (63%) versus high (66%) cHMGB1 expression (P=0.7441). Additionally, the risk of death was 0.8 (95% CI = 0.21–2.96). Conclusions: The cHMGB1 expression is associated with an increased tumor relapse in TNBC, not affecting patients' survival.

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Swaby, R. F., M. Huang, K. J. Ruth, E. A. Ross, Y. Gong, R. E. Page, G. M. Freedman, L. J. Goldstein et A. Di Cristofano. « Retrospective analysis of phosphorylation status of the estrogen receptor in patients with early stage disease ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 21034. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.21034.

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21034 Background: The AKT kinase, when phosphorylated to its activated form (pAKT), mediates many proliferative and survival effects of growth factor receptors such as members of the epidermal growth factor receptor (EGFR) family. Overexpression of AKT in breast neoplasms suggests that AKT activation is involved in breast cancer development and/or progression, and contributes to poor outcome. pAKT is frequently upregulated in Her-2/neu positive breast cancers. Activated AKT is able to phosphorylate in vitro serine 167 (pS167) of estrogen receptor alpha (ERa), resulting in ER-mediated transcriptional activity in the absence of estrogen and possibly contributing to tamoxifen resistance in ERa positive breast cancers. In addition, ERa is phosphorylated at S118 (pS118) by MAPK. Thus, it is possible that pAKT- mediated ERa phosphorylation is implicated in tumorigenesis and resistance to treatment with hormonal therapy in patients with breast cancer. Methods: Utilizing commercially available antibodies, IHC analysis of 125 paraffin-embedded, ERa positive, early breast cancer cases, stratified for stage, were tested for pAKT, PTEN, pS167, and pS118. Staining intensity and number of positive cells were assessed by 4 independent graders. Fisher's exact test was used to determine the significance of associations with a two-sided type I error of 5%. Results: Phosphorylation of AKT occurred in approximately one-half of cases. pS167 was phosphorylated in 66% of pAKT positive cases compared to 35% of pAKT negative cases (p<0.0001). When we analyzed nuclear pAKT staining, this association was more pronounced: 76% of pAKT(+) vs. 37% of pAKT(-) (p<0.0001). 69% of pS118(+) cases were pS167(+) compared to only 15% pS167(+) when pS118 was negative (p<0.0001). In approx. 32% of cases pAKT was present in both the cytoplasm and nucleus. 20% of samples had only cytoplasmic pAKT, while in 4% of cases pAKT was nuclear only, supporting the hypothesis that cytoplasmic phosphorylation of AKT may precede nuclear accumulation. Conclusions: Phosphorylation of pS167ERa is significantly associated with AKT activation (especially in the nucleus) in early breast cancer, supporting the hypothesis that these two events may be causally linked and contribute to breast cancer pathogenesis. No significant financial relationships to disclose.

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Depretto, Catherine, Anna Borelli, Alessandro Liguori, Gabriele Presti, Andrea Vingiani, Francesco Cartia, Claudio Ferranti et Gianfranco P. Scaperrotta. « Contrast-enhanced mammography in the evaluation of breast calcifications : preliminary experience ». Tumori Journal 106, n^o 6 (9 juin 2020) : 491–96. http://dx.doi.org/10.1177/0300891620919170.

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Aim: To evaluate the presence of contrast enhancement at the site of calcifications on contrast-enhanced mammography (CEM) and histopathologic results at vacuum-assisted biopsy (VAB), and to examine the association with lesion size and immunohistochemical characteristics, in order to assess disease aggressiveness in malignant lesions. Methods: A total of 34 patients with 36 clusters of suspicious calcifications (BI-RADS 4) were investigated with CEM before the scheduled VAB. We evaluated the presence or absence of enhancement, histologic diagnosis, and, in case of malignant lesions, their size and the expression of Ki-67. Results: In our case series, 15/36 (41.7%) lesions were malignant. In 7 cases, contrast enhancement was found at the site of calcifications. Data about size of lesions and immunohistochemical characterization were not available for all malignant cases. In 5 cases with CEM enhancement, all lesions were >5 mm and overexpressing Ki-67 (>20%); in 6 cases with no contrast enhancement, the lesions were <5 mm and with low Ki-67 values (<20%). Conclusion: Our preliminary study provides indications on the ability of CEM to recognize neoplasms larger than 5 mm, with high proliferative index (Ki-67 >20%), and frequently human epidermal growth factor receptor 2–positive. Our preliminary results suggest that CEM could detect aggressive malignancies. This could be the starting point for planning further studies with larger numbers of cases, in an attempt to reduce overdiagnosis and consequent overtreatment.

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Graham, Jeffrey, Debjani Grenier et Arjuna Ponnampalam. « Metastatic Breast Cancer in a Patient with Fanconi Anemia ». Blood 124, n^o 21 (6 décembre 2014) : 5164. http://dx.doi.org/10.1182/blood.v124.21.5164.5164.

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Abstract Fanconi anemia (FA) is a rare inherited disorder characterized by progressive bone marrow failure, congenital malformations and a propensity for developing malignancies at an early age. The underlying genetic defect in FA creates a state of cellular hypersensitivity to many traditional chemotherapy agents, making the treatment of malignancies in this population particularly challenging. We describe a 42-year-old female who presented with a solitary mass in her left breast. Core biopsy revealed an invasive ductal carcinoma that did not express estrogen (ER) or progesterone receptors (PR), but did express human epidermal growth factor receptor 2 (HER2). Staging work-up revealed diffuse skeletal metastatic disease. At her initial consultation with medical oncology, she was discovered to be pancytopenic. Further history revealed a sibling with aplastic anemia and that she had undergone chromosomal breakage testing for FA in the past, which was subsequently confirmed to be positive. She underwent a bone marrow aspirate and biopsy that showed metastatic marrow infiltration by non-hematopoietic cells. In addition there was morphological evidence of dyserythropoiesis and cytogenetic abnormalities on karyotyping, features suggestive of FA. She was initially started on trastuzumab monotherapy. Low dose radiation therapy was added due to local tumor progression. Combined HER2 directed therapy was to be implemented, but was held due to a functional decline in the patient. To date, she has not received definitive genetic testing to determine which FA subgroup she belongs to. This case highlights two important aspects of FA. The first is the inherent increase in susceptibility to neoplasms in this group, including solid tumors such as breast cancer. The genes associated with FA are involved in deoxyribonucleic acid (DNA) repair pathways, including mutations in the breast cancer susceptibility gene, BRCA2. The second is the heightened sensitivity to the toxic effects of many standard chemotherapy and radiation treatments. This creates unique challenges in the treatment of malignancies in this population and stresses the importance of targeted therapies. Disclosures No relevant conflicts of interest to declare.

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Shah, Parth, Shiva Murarka, Jacob Sands, Bhavna Mehta, Anupam Joshi, Khushbu Patel et Vipal Parmar. « Assessment of the clinical utility of chip-based digital PCR for HER2 assessment in formalin fixed paraffin-embedded breast carcinoma tissue. » Journal of Clinical Oncology 35, n^o 15_suppl (20 mai 2017) : e23120-e23120. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23120.

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e23120 Background: 15%-25% of breast cancer neoplasms exhibit Human epidermal growth factor receptor-2(HER2) amplification, as the driver mutation.Techniques to identify HER2 amplification include Immunohistochemistry (IHC) and Fluorescence in situ Hybridization (FISH). Digital PCR (dPCR) has been increasingly explored in determining HER2 status in cases of indeterminate results on IHC, mainly in archived samples. In this study, we aim to demonstrate the clinical utility of the Quantstudio 3D Digital PCR system to evaluate HER2 levels from Formalin Fixed Paraffin Embedded (FFPE) tissue with RNaseP as a control target. Methods: 61 tissue samples were analyzed by IHC and dPCR in parallel in a double blinded manner. IHC equivocal samples were reflexed to FISH and compared to the results obtained from dPCR. Samples suboptimal for IHC or FISH were satisfactorily processed by dPCR. dPCR results were analyzed on the Thermofisher Cloud platform. The general turnaround time(TAT) was about 2 and 3 days for IHC and FISH respectively with that of dPCR being 24 hours. Results: All 9 IHC positive and 35 negative samples had similar results on dPCR using an amplification ratio threshold for a positive result of 1.8. Of 17 IHC-equivocal samples, 5 resulted as positive, 10 negative and 2 as equivocal by dPCR. There was 100% concordance between the dPCR and FISH results. Two IHC equivocal samples that were unanalyzable by FISH were negative on dPCR Conclusions: Our results demonstrate that the chip based dPCR was non-inferior for HER2 detection in FFPE samples in a clinical setting. Superior TAT's and objective results were obtained compared to more subjective techniques like FISH and IHC even with low sample input. dPCR requires controls but no standards for calibration as it gives absolute copy numbers. Further study is needed to understand dPCR interpretation in cases of chromosomal aneuploidy. [Table: see text]

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Anja, Kerschen, Dano Hélène, Van Eeckhout Pascal, Marot Liliane et Van Bockstal Mieke. « Not All Cases of Mammary Paget’s Disease are Cytokeratin-7 Positive : A Challenging Diagnosis ! » International Journal of Surgical Pathology 29, n^o 6 (22 mars 2021) : 631–34. http://dx.doi.org/10.1177/10668969211002920.

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Mammary Paget’s disease accounts for 1% to 3% of all breast tumors and manifests as a chronic eczematous lesion of the areolar skin. It can occur without any underlying neoplasia or can be present in association with an underlying invasive and/or in situ carcinoma of the breast. The present report describes a challenging nipple punch biopsy showing an infiltration of the lower third to two-thirds of the epidermis by large, ovoid, neoplastic cells. The morphology was consistent with mammary Paget's disease, although immunohistochemistry for cytokeratin-7 (CK7) was repeatedly negative. This resulted in an initial misdiagnosis and, subsequently, a delay in the patient's follow-up. Additional immunohistochemistry for GATA binding protein 3 (GATA3) and human epidermal growth factor receptor 2 (HER2), as well as a second opinion of a breast pathologist, resulted in the diagnosis of mammary Paget's disease. The aim of this article is to raise awareness among pathologists and prevent them from misdiagnosing CK7-negative Paget disease of the breast.

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Soares, Nicolle Pereira, Alessandra Aparecida Medeiros, Igor De Paula Castro, Taís Meziara Wilson, Taís De Almeida Moreira et Mariana Batista Andrade. « Prognostic Factors in Canine Mammary Carcinomas and HER2 Expression Relationship ». Acta Scientiae Veterinariae 45, n^o 1 (9 juin 2017) : 9. http://dx.doi.org/10.22456/1679-9216.79791.

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Background: The human epidermal growth factor type 2 (HER2) receptor is a membrane glycoprotein tyrosine kinase. In woman, HER2 expression is diagnosed in 30% of breast carcinomas and it is associated with a worse prognosis, higher rate of recurrence and mortality. In the bitch, the HER2 overexpression in canine mammary tumors is still controversial and the prognostic value remains uncertain. Thus, we aimed to verify the HER2 expression in canine mammary carcinomas and relate it to the type and histological grade, lymph node metastasis and clinical staging.Materials, Methods & Results: Ninety bitches diagnosed with mammary carcinoma were included in this study. The inclusion criteria were bitches with complete clinical examination, thoracic radiographic examination and submitted unilateral or bilateral mastectomy. Ninety-nine samples of mammary carcinoma were used and the fragments of tumor and regional lymph nodes were fixed in 10% neutral formalin for histopathological and immunohistochemistry analysis. The lesions were evaluated by two pathologists and classified according to the type and histological grade. HER2 expression was performed by semi-quantitative analysis of the slides according to the HerceptTestTM (Dako) recommended score. Simple carcinomas were the most frequent (51.51%) followed by complex carcinomas (46.47%) and in situ carcinoma (2.02%). The histological grade of 97 carcinoma samples was attributed, except in situ carcinoma, 37 (38.14%) of the neoplasms were grade I, 50 (51.55%) grade II and only 10 (10.31%) tumors were classified as grade III. Forty bitches were submitted to clinical staging (TNM) and 42.50% of the bitches received staging in grade I and, 25% of the bitches staged in grade IV and V, with metastases. The HER2 expression, 13/99 samples (13.13%) received score +2, 19/99 (19.19%) score +1 and absence of marking (score 0) was identified in 67 samples (67.80 %). Immunostaining in hyperplastic or normal epithelial cells was evidenced, often in association with weak or moderate cytoplasmic labeling. Of the samples expressing +2 score for HER2 (n = 13), eight samples (17.39%) were complex carcinoma and five (9.80%) simple carcinomas. There was no relationship between HER2 immunostaining with age, tumor size, TNM, histological type, histological gradation, lymph node metastasis and distance. Animals with lymph node metastasis, as well as those diagnosed with distant metastasis, did not present HER2 expression in the tumors.Discussion: The simple carcinoma seems to be the most frequent type histological diagnosed in canine mammary carcinomas, followed by carcinoma in mixed tumor and complex carcinoma. Tubulopapillary carcinomas are more invasive in the female dogs as well as in the woman. Carcinomas grade I and II are more frequent and present a better prognosis for the dog. However, bitches with grade III carcinoma survived for a shorter time when compared to dogs with grade I or II tumors. A factor that may have contributed to the lower number of bitches at worst prognostic stage (EC IV and V) is the current owners’ awareness that they have sought veterinary help earlier, as soon as they detect small nodules in mammary gland. Overexpression of HER2 in women breast cancer is diagnosed in 20-30% of cases, whereas in bitches, this expression is variable. Also the different percentages of canine HER2 immunostaining are due to the lack of standardization for the analysis of the immunostaining, the immunohistochemical techniques employed and the non-specificity of the HER2 antibody. In canine mammary carcinomas the HER2 expression in low and this immunostaining is not related to other established prognostic factors. This study reinforces the hypothesis put forward by other authors that in the bitch the expression of HER2 may not be related to malignancy and tumor progression.

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Grupka, Nichon L., Kelly C. Lear-Kaul, Bette K. Kleinschmidt-DeMasters et Meenakshi Singh. « Epidermal Growth Factor Receptor Status in Breast Cancer Metastases to the Central Nervous System ». Archives of Pathology & ; Laboratory Medicine 128, n^o 9 (1 septembre 2004) : 974–79. http://dx.doi.org/10.5858/2004-128-974-egfrsi.

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Abstract Context.—The development of drug therapies (ZD1839) targeting epidermal growth factor receptor (EGFR) offers a pragmatic reason for exploring expression of EGFR in breast cancer, particularly metastatic breast cancer. There is a reported synergistic relationship between trastuzumab and ZD1839 therapy in patients with breast cancer. Although EGFR is the preferred dimerization partner for HER-2, it is unclear whether expression of these 2 interrelated receptors in a given patient with breast cancer would be parallel or mutually exclusive. Objectives.—To assess EGFR status in primary breast carcinoma versus metastatic central nervous system (CNS) sites and to compare results with HER-2/neu status in the same tumor. Design.—Central nervous system metastases (n = 51) from 33 patients and corresponding primary breast cancer specimens, when available (n = 11), were immunohistochemically stained for EGFR using a monoclonal mouse anti-EGFR antibody (clone 31G7) that recognizes both the wild-type form and the 145-kd variant III form of EGFR. The sections were evaluated by visual and image analysis techniques, and results were compared to previously assessed HER-2/neu status. Results.—Epidermal growth factor receptor expression was found in CNS metastases from 39% of patients, with 82% concordance between the EGFR status of the primary breast and metastatic sites, and 92% concordance between the EGFR status among multiple CNS metastases in a given patient. Epidermal growth factor receptor and HER-2/neu status were concordant at the primary site in only 45% of patients. Additionally, EGFR and HER-2/neu status were concordant among multiple CNS metastases per individual case in only 45% of patients. Conclusion.—Thirty-nine percent of patients with metastatic breast cancer express EGFR, with parallel expression between metastatic sites and the primary neoplasm in 82% of the cases. The discordance in 18% of the cases, however, suggests that anti-EGFR agents might not show equal efficacy against metastatic tumor deposits and the primary tumor within a given patient. An additional corollary for pathologists based on this nonhomogeneity of receptor expression is that both the primary breast and multiple metastatic tumor deposits may need to be individually assessed for EGFR status. In our study, most metastatic tumor deposits showed expression for either EGFR or HER-2/neu, and less often for both, implying that drug therapies could be individualized for patients based on test results for both receptors.

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Lin, Yi, Sio In Wong, Yuzhou Wang, Chileong Lam et Xianghong Peng. « Periampullary Metastases from Breast Cancer : A Case Report and Literature Review ». Case Reports in Oncological Medicine 2019 (9 janvier 2019) : 1–6. http://dx.doi.org/10.1155/2019/3479568.

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We presented a metastatic breast cancer case who was afflicted with obstructive jaundice caused by an ampullary neoplasm. Since jaundice due to periampullary metastasis from breast cancer was a rare entity, a literature review of similar cases through the PubMed database was done. A total of 23 additional cases were found. Among these 24 cases, 5 presented with periampullary metastasis synchronously with the diagnosis of breast cancer, while 19 had metachronous periampullary metastasis with an interval ranging between 1.3 and 23 years from the initial diagnosis of breast cancer to the emergence of jaundice. It is intriguing to establish a differential diagnosis for common bile tract stricture prior to tissue biopsy, even with diagnostic workups including serum tumor markers, MRI plus MRCP, ERCP with intraductal brushing, and endoscopic ultrasound, in that the clinical, radiological, and endoscopic findings of metastatic lesions overlapped extensively with those found with primary periampullary malignancies. An immunohistochemical portfolio including cytokeratin7/20 (CK7/20), homeobox protein CDX2, human epidermal growth factor receptor 2 (HER2/neu), estrogen receptor alfa (ERα), progesterone receptor (PgR), mammaglobin, gross cystic disease fluid protein-15 (GCDFP-15), and transacting T-cell-specific transcription factor (GATA-3) was helpful for differential diagnosis among cases with ambiguous microscopic features.

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Shingu, Kiyoshi, Tokiko Ito, Gengo Kaneko et Nobuo Itoh. « Primary Acinic Cell Carcinoma of the Breast : A Clinicopathological and Immunohistochemical Study ». Case Reports in Oncological Medicine 2013 (2013) : 1–5. http://dx.doi.org/10.1155/2013/372947.

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Acinic cell carcinoma of the breast is an extremely rare, malignant neoplasm characterized by widespread acinar cell-like differentiation and clinically low-grade malignancy. Herein, we report a case of acinic cell carcinoma of the breast in a 41-year-old woman. The tumor was poorly demarcated but had a firm consistency. It was removed with lumpectomy, and sentinel lymph node biopsy was performed to check for metastasis. Microscopically, the tumor showed an infiltrative growth pattern with a combination of solid, trabecular, and microglandular areas. Many of the tumor cells had abundant clear vacuolated cytoplasm containing zymogen-typed granules which resemble acinar cells of the salivary glands. The immunohistochemical profile of the tumor was also similar to that of salivary gland acinic cell carcinoma: the tumor cells were positive for amylase, lysozyme,α-1-antichymotrypsin, S-100 protein, and epithelial membrane antigen and negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. She received postoperative chemoradiation therapy and has been well for 3 years since surgery. As studies on large series are lacking, further studies are needed to elucidate the biological characteristics of acinic cell carcinoma of the breast.

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Sierko, Ewa, Lech Zimnoch, Leszek Kozlowski, Walter Kisiel et Marek Wojtukiewicz. « Immunohistochemical localization of tissue factor pathway inhibitor-2 in human tumor tissue ». Thrombosis and Haemostasis 90, n^o 07 (2003) : 140–46. http://dx.doi.org/10.1055/s-0037-1613610.

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SummaryThe progression of neoplasms is frequently associated with thromboembolic complications. Coagulation proteins, particularly tissue factor (TF), have been shown to play a role in tumor growth and metastatic dissemination. TFPI is the principal inhibitor of TF-dependent pathway of blood coagulation, but previous studies failed to detect antigenic TFPI in cancer tissue. Recently, a second inhibitor of tissue factor dependent pathway, TFPI-2 (also known as placental protein 5 [PP5] or matrix-associated serine protease inhibitor [MSPI]), has been described. Information on the presence of TFPI-2 within the malignant tumor tissue still remains obscure, and thus the aim of this study was to evaluate the expression of TFPI-2 in loco in several different neoplasms. TFPI-2 expression was demonstrated by immu-nohistochemical procedures in neoplastic cells of laryngeal, breast, gastric, colon, pancreatic, renal and endometrial cancer, as well as glial neoplasms. The intensity of staining was not uniform, with higher intensity in more differentiated tumors. G3 breast, gastric, endometrial and colon cancer cells revealed populations of cells that were either TFPI-2 positive or negative. Gastric and renal cancer tissue exhibited the presence of TFPI-2 in tumor infiltrating macrophages. TFPI-2 was also observed in normal tissue of the breast, stomach, colon and pancreas. These data demonstrate that the expression of TFPI-2 diminishes with an increasing degree of malignancy, which may suggest a role for TFPI-2 in the maintenance of tumor stability and inhibition of the growth of neoplasms.

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Qattan, Amal. « Metabolic Reprogramming of Triple-Negative Breast Cancer : The Role of miRNAs ». microRNA Diagnostics and Therapeutics 3, n^o 1 (20 décembre 2017) : 1–8. http://dx.doi.org/10.1515/micrnat-2017-0001.

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AbstractMicroRNAs (miRNAs) are well known to influence the expression of the genes that regulate critical cellular functions. Various reports have suggested that they play critical roles in breast cancer metabolism through the regulation of various metabolic pathways, including the metabolism of glucose, lipids, glycolysis and the mitochondrial tricarboxylic acid cycle (TCA). miRNAs regulate the metabolic process by targeting key molecules (enzymes, kinases transporters) or by modifying the expression of key transcription molecules. In addition, miRNAs can indirectly regulate mRNA translation by targeting chromatin-remodeling enzymes. Furthermore, miRNAs influence the expression of both oncogenes and tumor suppressors and have a major impact on PI3K/AKT, HIF, and MYC signal transduction, which contributes to the metabolic phenotype in human cancer. Although human epidermal growth factor and endocrine therapies have been effective in treating breast cancer, for locally advanced and distant metastases mortality remains high. Drug resistance and recurrence remain major hurdles for advanced breast cancer therapy. Given the critical influence of metabolic reprogramming in the progression of neoplasm, tumorigenesis and metastasis, research should focus on novel targets of metabolic enzymes to reverse drug resistance and improve overall survival rates. Blocking the miRNAs that contribute to metabolic reprogramming or the use of exogenous miRNAs as antisense oligonucleotides, may be an effective way to treat aggressive, chemo-resistant cancers. This review summarizes current knowledge on the mechanism of action of miRNAs in altering the metabolism of cancer cells and presents possible therapeutic approaches to treating breast cancers that are resistant to current drugs.

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Fiori Lopes, Leandra, Roberta Losi Guembarovski, Alda Losi Guembarovski, Marina Okuyama Kishima, Clodoaldo Zago Campos, Julie Massayo Maeda Oda, Carolina Batista Ariza, Karen Brajão de Oliveira, Sueli Donizete Borelli et Maria Angelica Ehara Watanabe. « FOXP3 Transcription Factor : A Candidate Marker for Susceptibility and Prognosis in Triple Negative Breast Cancer ». BioMed Research International 2014 (2014) : 1–7. http://dx.doi.org/10.1155/2014/341654.

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Triple negative breast cancer (TNBC) is a relevant subgroup of neoplasia which presents negative phenotype of estrogen and progesterone receptors and has no overexpression of the human epidermal growth factor 2 (HER2). FOXP3 (forkhead transcription factor 3) is a marker of regulatory T cells (Tregs), whose expression may be increased in tumor cells. This study aimed to investigate a polymorphism (rs3761548) and the protein expression of FOXP3 for a possible involvement in TNBC susceptibility and prognosis. Genetic polymorphism was evaluated in 50 patients and in 115 controls by allele-specific PCR (polymerase chain reaction). Protein expression was evaluated in 38 patients by immunohistochemistry. It was observed a positive association for homozygous AA (OR = 3.78; 95% CI = 1.02–14.06) in relation to TNBC susceptibility. Most of the patients (83%) showed a strong staining for FOXP3 protein in the tumor cells. In relation to FOXP3-positive infiltrate, 47% and 58% of patients had a moderate or intense intratumoral and peritumoral mononuclear infiltrate cells, respectively. Tumor size was positively correlated to intratumoral FOXP3-positive infiltrate (P=0.026). In conclusion, since FOXP3 was positively associated with TNBC susceptibility and prognosis, it seems to be a promising candidate for further investigation in larger TNBC samples.

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Ribeiro-Silva, A., H. Becker de Moura, F. Ribeiro do Vale et S. Zucoloto. « The Differential Regulation of Human Telomerase Reverse Transcriptase and Vascular Endothelial Growth Factor May Contribute to the Clinically More Aggressive Behavior of P63-Positive Breast Carcinomas ». International Journal of Biological Markers 20, n^o 4 (octobre 2005) : 227–34. http://dx.doi.org/10.1177/172460080502000405.

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p63, a p53 homologue, is a myoepithelial cell marker in the normal mammary gland but p63-positive neoplastic cells may be found in up to 11% of invasive breast carcinomas. This study aims to verify the relationship between p63 expression and several clinicopathological features and tumor markers of clinical significance in breast pathology including key regulators of the cell cycle, oncogenes, apoptosis-related proteins, metalloproteinases and their inhibitors. Immunohistochemistry with 27 primary antibodies was performed in 100 formalin-fixed paraffin-embedded samples of invasive ductal carcinomas. p63-positive cells were found in 16% of carcinomas. p63-positive carcinomas were poorly differentiated, hormone receptor-negative neoplasms with a high proliferation rate. p63 also correlated with advanced pathological stage, tumor size, and the expression of human telomerase reverse transcriptase (hTERT), tissue inhibitor of matrix metalloproteinase 1 (TIMP1) and vascular endothelial growth factor (VEGF). The expression of TIMP1 suggests that the anti-proteolytic stimuli may be preponderant in p63-positive carcinomas. hTERT activity is associated with nodal metastases and cellular proliferation. VEGF regulates angiogenesis, which is also a fundamental event in the process of tumor growth and metastatic dissemination. Thus, the differential regulation of hTERT and VEGF in p63-positive breast carcinomas may contribute to the clinically more aggressive behavior of these neoplasms.

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Brachtel, Elena F., Jennifer E. Rusby, James S. Michaelson, L. Leon Chen, Alona Muzikansky, Barbara L. Smith et Frederick C. Koerner. « Occult Nipple Involvement in Breast Cancer : Clinicopathologic Findings in 316 Consecutive Mastectomy Specimens ». Journal of Clinical Oncology 27, n^o 30 (20 octobre 2009) : 4948–54. http://dx.doi.org/10.1200/jco.2008.20.8785.

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Purpose Although breast-conserving surgery is a standard approach for patients with breast cancer, mastectomy often becomes necessary. Surgical options now include nipple-sparing mastectomy but its oncological safety is still controversial. This study evaluates frequency and patterns of occult nipple involvement in a large contemporary cohort of patients with the retroareolar margin as possible indicator of nipple involvement. Patients and Methods Three hundred sixteen consecutive mastectomy specimens (232 therapeutic, 84 prophylactic) with grossly unremarkable nipples were evaluated by coronal sections through the entire nipple and subareolar tissue. Extent and location of nipple involvement by carcinoma was assessed with the tissue deep to the skin as potential retroareolar en-face resection margin. Results Seventy-one percent of nipples from therapeutic mastectomies showed no pathologic abnormality, 21% had ductal carcinoma in situ (DCIS), invasive carcinoma (IC), or lymphovascular invasion (LVI), and 8% lobular neoplasia (lobular carcinoma in situ). Human epidermal growth factor receptor 2 amplification, tumor size, and tumor-nipple distance were associated with nipple involvement by multivariate analysis (P = .0047, .0126, and .0176); histologic grade of both DCIS (P = .002) and IC (P = .03), LVI (P = .03), and lymph node involvement (P = .02) by univariate analysis. Nipple involvement by IC or DCIS was identified in the retroareolar margin with a sensitivity of 0.8 and a negative predictive value of 0.96. None of the 84 prophylactic mastectomies showed nipple involvement by IC or DCIS. Conclusion Nipple-sparing mastectomy may be suitable for selected cases of breast carcinoma with low probability of nipple involvement by carcinoma and prophylactic procedures. A retroareolar en-face margin may be used to test for occult involvement in patients undergoing nipple-sparing mastectomy.

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Vecchia, Carlo La. « Tomatoes, Lycopene Intake, and Digestive Tract and Female Hormone-Related Neoplasms ». Experimental Biology and Medicine 227, n^o 10 (novembre 2002) : 860–63. http://dx.doi.org/10.1177/153537020222701004.

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Tomato consumption showed a consistent inverse relation with the risk of digestive tract neoplasms in Italy in an integrated series of studies conducted in the 1980s. Another series of case-control studies was conducted between 1992 and 1999 in different areas of Italy. Cases were patients below age 80 with incident, histologically confirmed cancer of the oral cavity and pharynx (n = 754), esophagus (n = 304), colorectum (n = 1953), breast (n = 2529), and ovary (n = 1031). The comparison group involved, overall, over 5000 patients below age 80 with acute, non-neoplastic, nonhormone-related diseases, unrelated to long-term diet modifications and admitted to the same network of hospitals. Information was collected in hospital by trained interviewers using a validated food frequency questionnaire, including 78 foods or groups of foods, various alcoholic beverage, and fat-intake pattern. The multivariate relative risk (RR) of oral, pharyngeal, and esophageal cancer decreased across subsequent levels of lycopene intake to reach 0.7 (95% confidence interval [CI] 0.4–1.0) for oral and pharyngeal, and 0.7 (95% CI 0.4–1.1) for esophageal cancer in the highest quintile of intake. Both trends in risk were of borderline statistical significance. With reference to colorectal, breast, and ovarian cancer, although no consistent association was observed for lycopene (RR = 1.0 for colorectal, 1.2 for breast, and 1.1 for ovary in the highest quintile), tomato Intake was inversely and significantly related with colorectal cancer (RR = 0.8). The inverse relation between lycopene and upper digestive tract neoplasms was not explained by alcohol or tobacco, sociodemographic factors, or total energy Intake. The interpretation of such an inverse relation, however, remains open to discussion because it may be related to an effect of lycopene due to its antioxidant effect and/or a potential role of lycopene in decreasing Insulin growth factor I, which is a promoter in the process of carcinogenesis.

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Tawfeik, Amany M., Ahmed Mora, Ahmed Osman, Manar M. Moneer, Nabila El-Sheikh et Mohamed Elrefaei. « Frequency of CD4+ regulatory T cells, CD8+ T cells, and human papilloma virus infection in Egyptian Women with breast cancer ». International Journal of Immunopathology and Pharmacology 34 (janvier 2020) : 205873842096682. http://dx.doi.org/10.1177/2058738420966822.

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Several subsets of regulatory CD4+ T cells (CD4+ Tregs) have been described in peripheral blood and tumor microenvironment of breast cancer (BC) patients and may play a role in the progression of BC. High-risk human papilloma virus (HR-HPV) has a causal role in cervical, head, and neck tumors but the role of HR-HPV in evoking neoplasia in BC is still unclear. In this study we assessed the prevalence of CD4+CD25+ FOXP3+ regulatory T cells (CD4+Tregs) and CD3+ CD8+ T cells by flow cytometry in peripheral blood from a total of 55 Egyptian women, including 20 treatment-naïve BC, 15 with breast benign lesions (BBL), and 20 healthy volunteers (HV). HR-HPV genotypes type 16, 18, and 31 were investigated in breast tissue from all BC and BBL patients using Real-Time PCR. HR-HPV was detected in 4/20 (20%) and 0/15 (0%) BC and BBL patients respectively. The frequency of CD4+ Tregs was significantly higher in BC compared to BBL and HV, ( P < 0.001). In addition, we observed a significantly higher frequency of CD3+ CD8+ T cells in peripheral blood of patients with late stage III BC compared to early stage I and II BC ( P = 0.011). However, there was no significant association between the ratio of CD8+ T cell to CD4+ Tregs frequencies and the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). These results lead us to postulate that the association between the frequency of CD4+ Tregs and CD8+ T cells in the peripheral blood may be a prognostic or predictive parameter in Egyptian women with BC. In addition, HR-HPV infection may be implicated in the development of some types of BC in Egyptian women.

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Astanehe, A., et M. Finkbeiner. « Profiling YB-1 responsive genes in basal-like breast cancer cells by ChIP-on-chip reveals direct binding to PIK3CAs ». Clinical & ; Investigative Medicine 30, n^o 4 (1 août 2007) : 73. http://dx.doi.org/10.25011/cim.v30i4.2840.

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Purpose: Basal-like breast cancers (BLBC) are typically very aggressive and they are also prone to a high rate of recurrence. We recently identified the transcription factor Y-box binding protein-1 (YB-1) as an important component of BLBC by screening breast tumour tissue microarrays. YB-1 is well known for its ability to confer chemotherapy resistance and to promote the growth of a wide range of cancer cell types. The breast cancer cell line SUM149 was characterized by us as having all the hallmarks of BLBC including a lack of the estrogen, progesterone, and Her-2 receptors. We also find that they express high levels of the epidermal growth factor receptor, a YB-1 responsive gene. We performed a genome-wide promoter screen of the possible YB-1 responsive genes using the NimbleGen ChIP-on-chip (COC) platform to begin to understand how this oncogene regulates the growth of basal-like breast cancer cells. YB-1 was found to bind to ~6,700 human promoters. Several members of the phosphatidylinositol-3-kinase (PI3K) pathway were identified (p110a, p85, Akt-2, ILK). Of particular interest was the identification of PIK3CA, the gene that codes for the p110a catalytic subunit of PI3K. PI3K, a lipid kinase with important roles in neoplasia, phosphorylates membrane inositol lipids resulting in activation of downstream effectors that are involved in cellular responses such as cell proliferation, survival, metabolism, and cytoskeletal reorganization. Many studies have suggested importance of the role of PI3K signaling in various types of cancer. Approximately 20% of breast cancers harbour somatic activating mutations in PIK3CA, and about 8% have amplification of PIK3CA. The remainder of the cancers have elevated levels of PI3K via other mechanisms including increased transcription. Methods & Results: Here we propose that YB-1 overexpression in cancer leads to increased PIK3CA transcription via direct binding to the promoter. To extend our COC findings, we knocked down YB-1 with siRNA and observed a concomitant loss in p110a by immunoblotting. We have recently identified two alternate PIK3CA transcriptional start sites (exon 1a and 1b) and two alternate PIK3CA promoters (promoter 1a and 1b). We mapped potential YB-1 binding sites on PIK3CA promoters 1a and 1b, and identified five putative YB-1 binding sites within promoter 1a and one putative binding site within promoter 1b. We further performed traditional ChIP and EMSA to confirm the interaction of YB-1 with the putative binding sites on PIK3CA promoter, and determined that YB-1 binds to promoter 1a, but not to promoter 1b. Conclusion:The demonstration that YB-1 binds directly to the PIK3CA promoter and induces its activity identifies a novel mechanism whereby activation of YB-1 and subsequent up-regulation of PIK3CA may contribute to the pathophysiology, outcomes and therapeutic responsiveness of breast cancer.

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Decensi, Andrea, Chris Robertson, Aliana Guerrieri-Gonzaga, Davide Serrano, Massimiliano Cazzaniga, Serena Mora, Marcella Gulisano et al. « Randomized Double-Blind 2 × 2 Trial of Low-Dose Tamoxifen and Fenretinide for Breast Cancer Prevention in High-Risk Premenopausal Women ». Journal of Clinical Oncology 27, n^o 23 (10 août 2009) : 3749–56. http://dx.doi.org/10.1200/jco.2008.19.3797.

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Purpose Tamoxifen and fenretinide are active in reducing premenopausal breast cancer risk and work synergistically in preclinical models. The authors assessed their combination in a two-by-two biomarker trial. Patients and Methods A total of 235 premenopausal women with pT1mic/pT1a breast cancer (n = 21), or intraepithelial neoplasia (IEN, n = 160), or 5-year Gail risk ≥ 1.3% (n = 54) were randomly allocated to either tamoxifen 5 mg/d, fenretinide 200 mg/d, their combination, or placebo. We report data for plasma insulin-like growth factor I (IGF-I), mammographic density, uterine effects, and breast neoplastic events after 5.5 years. Results During the 2-year intervention, tamoxifen significantly lowered IGF-I and mammographic density by 12% and 20%, respectively, fenretinide by 4% and 10% (not significantly), their combination by 20% and 22%, with no evidence for a synergistic interaction. Tamoxifen increased endometrial thickness principally in women becoming postmenopausal, whereas fenretinide decreased endometrial thickness significantly. The annual rate of breast neoplasms (n = 48) was 3.5% ± 1.0%, 2.1% ± 0.8%, 4.7% ± 1.3%, and 5.2% ± 1.3% in the tamoxifen, fenretinide, combination, and placebo arms, respectively, with hazard ratios (HRs) of 0.70 (95% CI, 0.32 to 1.52), 0.38 (95% CI, 0.15 to 0.90), and 0.96 (95% CI, 0.46 to 1.99) relative to placebo (tamoxifen × fenretinide adverse interaction P = .03). There was no clear association with tumor receptor type. Baseline IGF-I and mammographic density did not predict breast neoplastic events, nor did change in mammographic density. Conclusion Despite favorable effects on plasma IGF-I levels and mammographic density, the combination of low-dose tamoxifen plus fenretinide did not reduce breast neoplastic events compared to placebo, whereas both single agents, particularly fenretinide, showed numerical reduction in annual odds of breast neoplasms. Further follow-up is indicated.

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Sevcikova, Katarina, Zuo Zhuang, Guillermo Garcia-Manero, Ricardo Alvarez, Hagop M. Kantarjian, Mego Michal, Constance Albarracin et al. « Therapy-Related Myeloid Neoplasms in Breast Cancer Patients : A Single-Institution Report of 150 Cases ». Blood 124, n^o 21 (6 décembre 2014) : 962. http://dx.doi.org/10.1182/blood.v124.21.962.962.

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Abstract Introduction: Patients who receive chemotherapy and/or radiation therapy for breast cancer (BCA) are at risk for developing therapy-related myeloid neoplasms (t-MN). In fact, BCA is one of the most common malignant solid tumors among patients with t-MN. Nonetheless, the association between t-MN features and the demographic, biologic, and therapeutic characteristics of patients with BCA remain poorly characterized. The aim of this study was to assess the factors associated with t-MN in BCA patients and determine the features and outcomes of t-MN in this patient group. Methods: We conducted a retrospective analysis of BCA patients who developed t-MN seen at The University of Texas M.D. Anderson Cancer Center between January 1997 and April 2013. As defined in the current WHO classification, t-MN includes therapy-related acute myeloid leukemia (t-AML), myelodysplastic syndrome (t-MDS), and myelodysplastic/myeloproliferative neoplasms (t-MDS/MPN). The study inclusion criteria included receipt of neoadjuvant or adjuvant chemotherapy and/or radiation therapy for BCA with subsequent development of t-MN. Results: All patients (n=150) were women with a median age of 57 years (range, 26-79 years) at the time of BCA diagnosis (64 at time of t-MN; range, 29-84 years). At presentation with BCA, stage ranged from 0 to 3. In addition to surgery, 93 (62%) patients were treated with combination chemotherapy and radiation therapy, 30 (20%) with radiation therapy alone, and 27 (18%) with chemotherapy alone. The median interval between BCA and t-MN was 57 months (range, 8-374 months); 54 months and 57 months respectively for patients who received chemotherapy alone or radiation therapy alone. At the time of t-MN diagnosis, 90 (60%) patients had t-AML, 56 (37%) t-MDS, and 4 (3%) t-MDS/MPN. Among patients with t-MDS and t-MDS/MPN, 26 (22%) developed t-AML after a median of 13.9 months (range, 2.3-69.6 months). Notably, development of t-MN among patients with BCA was associated with a body-mass index <25 (p=0.030) and with HER2-positive BCA (14/55; p=0.037). Among all patients with t-MN, those with MLL gene (11q23) rearrangement had a worse overall survival (OS) (p=0.017) while those with favorable recurrent chromosomal translocations (PML/RARA; CBFB-MYH11; RUNX1/RUNX1T1) had a better OS (p=0.001). Patients who received allogeneic stem-cell transplant (SCT) for t-MN had a better OS calculated from the onset of t-MN compared to those who did not (p=0.018). By multivariate analysis, factors associated independently with OS calculated from the time of BCA diagnosis included age at BCA diagnosis (p<0.001), BMI category (p=0.016), chemotherapy for BCA (p=0.027), anti-HER2 therapy (p=0.003), and growth factor administration (p=0.023). Notable factors associated independently with OS calculated from the time of t-MN diagnosis included MLL rearrangement (p=0.014), favorable recurrent balanced translocations (p=0.006), and SCT (p=0.010). Conclusions: Patients with BCA who have a BMI <25 and are HER2-positive appear to be at a higher risk for t-MN. In addition, the OS of BCA patients in our study group appears to be associated with BMI and anti-HER2 therapy. Disclosures No relevant conflicts of interest to declare.

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Lyou, Yung, Emily Barber, Rita Mehta, Thomas Lee, Wamda Goreal et Ritesh Parajuli. « Radiation-Associated Angiosarcoma of the Breast : A Case Report and Literature Review ». Case Reports in Oncology 11, n^o 1 (6 avril 2018) : 216–20. http://dx.doi.org/10.1159/000488314.

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In the last couple of decades, breast conservation therapy, which utilizes a combination of surgery, radiotherapy, and endocrine or chemotherapy, has become the standard of care for treating early-stage breast cancer. This practice has been greatly beneficial in the improvement of the patient’s quality of life but has also led to the increased use of radiotherapy and associated soft-tissue sarcomas, with angiosarcoma being the most common malignancy. Radiation-associated angiosarcoma (RAS) of the breast is a rare phenomenon, which has been reported to occur in approximately 0.9 out of 1,000 cases, with a reported onset as late as 23 years following radiotherapy. Here we report 2 cases of RAS that occurred within 6 and 13 years following radiotherapy of their primary breast lesion. We discuss the diagnostic and therapeutic challenges regarding this disease and review the current literature. This case report serves as cautionary lessons on the importance of considering RAS of the breast in the differential diagnosis during evaluation for recurrent breast neoplasms. Ongoing clinical trials using combinations of vascular endothelial growth factor inhibitors and chemotherapy may provide future avenues of treatment for this difficult-to-treat disease.

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Wardley, Andrew, Javier Cortes, Louise Provencher, Kathy Miller, A. Jo Chien, Hope S. Rugo, Joyce Steinberg et al. « The efficacy and safety of enzalutamide with trastuzumab in patients with HER2+ and androgen receptor-positive metastatic or locally advanced breast cancer ». Breast Cancer Research and Treatment 187, n^o 1 (16 février 2021) : 155–65. http://dx.doi.org/10.1007/s10549-021-06109-7.

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Abstract Purpose Androgen receptor (AR) expression occurs in up to 86% of human epidermal growth factor receptor 2-positive (HER2+) breast cancers. In vitro, AR inhibitors enhance antitumor activity of trastuzumab, an anti-HER2 antibody, in trastuzumab-resistant HER2+ cell lines. This open-label, single-arm, phase II study evaluated the efficacy and safety of enzalutamide, an AR-signaling inhibitor, in patients with advanced HER2+ AR+ breast cancer previously treated with trastuzumab. Methods Eligible patients had measurable or non-measurable evaluable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, Eastern Cooperative Oncology Group status ≤ 1, no history of brain metastases, and previously received ≥ 1 anti-HER2 regimen for advanced disease. Patients received 160 mg oral enzalutamide daily and 6 mg/kg intravenous trastuzumab every 21 days until disease progression or unacceptable toxicity. Primary end point was clinical benefit rate at 24 weeks (CBR24); secondary end points included progression-free survival (PFS) and safety. Results Overall, 103 women were enrolled [median age 60 years (range 34–83)]; 62% had received ≥ 3 lines of prior anti-HER2 therapy. CBR24, comprising patients with confirmed partial responses (5%) and durable stable disease at 24 weeks (19%), was 24% in the efficacy evaluable set (n = 89). CBR24 did not seem related to AR-expression levels or hormone receptor status. Median PFS was 3.4 months (95% confidence interval 2.0–3.8). Overall, 97 (94%) patients experienced treatment-emergent adverse events (TEAEs), with fatigue most common (34%). Dyspnea (4%) and malignant neoplasm progression (3%) were the only TEAEs grade ≥ 3 reported in ≥ 3 patients. 22 patients (21%) reported serious TEAEs. Four patients (4%) experienced fatal, non-drug-related TEAEs. Conclusions Enzalutamide plus trastuzumab was well tolerated, and a subset of patients in this heavily pretreated population had durable disease control. Determination of biomarkers is needed to identify patients most likely to benefit from this combination. ClinicalTrials.gov number NCT02091960

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Zarychta, Elżbieta, Barbara Ruszkowska-Ciastek, Kornel Bielawski et Piotr Rhone. « Stromal Cell-Derived Factor 1α (SDF-1α) in Invasive Breast Cancer : Associations with Vasculo-Angiogenic Factors and Prognostic Significance ». Cancers 13, n^o 8 (18 avril 2021) : 1952. http://dx.doi.org/10.3390/cancers13081952.

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(1) Background: Tumour angiogenesis is critical for the progression of neoplasms. A prospective study was designed to examine the utility of stromal cell-derived factor 1α (SDF-1α) and selected vasculo-angiogenic parameters for estimating the probability of disease relapse in 84 primary, operable invasive breast cancer (IBrC) patients (40 (48%) with stage IA and 44 (52%) with stage IIA and IIB). (2) Methods: We explored the prognostic value of the plasma levels of SDF-1α, vascular endothelial growth factor A (VEGF-A), the soluble forms of VEGF receptors type 1 and 2, and the number of circulating endothelial progenitor cells (circulating EPCs) in breast cancer patients. The median follow-up duration was 58 months, with complete follow-up for the first event. (3) Results: According to ROC curve analysis, the optimal cut-off point for SDF-1α (for discriminating between patients at high and low risk of relapse) was 42 pg/mL, providing 57% sensitivity and 75% specificity. Kaplan–Meier curves for disease-free survival (DFS) showed that concentrations of SDF-1α lower than 42 pg/dL together with a VEGFR1 lower than 29.86 pg/mL were significantly associated with shorter DFS in IBrC patients (p = 0.0381). Patients with both SDF-1α lower than 42 pg/dL and a number of circulating EPCs lower than 9.68 cells/µL had significantly shorter DFS (p = 0.0138). (4) Conclusions: Our results imply the clinical usefulness of SDF-1α, sVEGFR1 and the number of circulating EPCs as prognostic markers for breast cancer in clinical settings.

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Sierko, Ewa, Rodryg Ramlau, Lech Zimnoch, George J. Broze et Marek Wojtukiewicz. « Expression of Protein Z-Dependent Protease Inhibitor (ZPI) In Situ in Different Malignant Tumors. » Blood 104, n^o 11 (16 novembre 2004) : 3959. http://dx.doi.org/10.1182/blood.v104.11.3959.3959.

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Abstract Cancer progression is often associated with thromboembolic complications. Coagulation factors and inhibitors influence various processes involved in malignant tumor growth and metastatic dissemination. Recently a new coagulation inhibitor - protein Z-dependent protease inhibitor (ZPI) has been characterized. ZPI is a plasma proteinase inhibitor in the serpin superfamily. ZPI inhibits factor Xa activity in the presence of calcium and phospholipids. Protein Z augments its activity by more than 1000-fold. ZPI also attenuates the activity of factor XIa in the reaction which does not require the presence of calcium and phospholipids. ZPI inhibits the coagulation response prior to the formation of the prothrombinase complex. Up to now the data on the presence of ZPI in malignant tumors are obscure. The purpose of the study was to elucidate the solid phase interactions between various types of maligant tissues and ZPI that may contribute to tumor progression. The tissues from colon, breast, gastric, renal, pancreatic, endometrial carcinoma, non-small cell lung cancer (NSCLC) as well as from glial neoplasms were obtained at surgical resection during radical treatment. The patients undergoing surgery have not received any previous antineoplastic therapy. Tumor fragments were processed acc. to AMeX method and then embedded in paraffin. Immunohistochemical studies (avidin-biotin complex-ABC - technique) were performed using a monoclonal antibody against ZPI. Expression of ZPI was observed in cancer cell bodies of colon, breast, gastric, renal, endometrial, pancreatic cancer, NSCLC and glial neoplasms. The staining intensity for ZPI was irregular: both strong and weak expression of ZPI was observed. Moreover, various percentages of ZPI-positive cancer cells were revealed in different specimens of examined tissues. Macrophages and mucin also revealed expression of ZPI in the case of colon cancer. The presence of ZPI was demonstrated in the stroma of renal cancer. The obtained results suggest that ZPI being an inhibitor of coagulation might additionally play a role in the regulation of cancer progression.

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Sierko, Ewa, Piotr Tokajuk, Rodryg Ramlau, Lech Zimnoch, Walter Kisiel et Marek Wojtukiewicz. « Localization of Protein Z (PZ) In Situ in Human Neoplastic Tissues. » Blood 104, n^o 11 (16 novembre 2004) : 3958. http://dx.doi.org/10.1182/blood.v104.11.3958.3958.

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Abstract Tumor cells synthesize and release procoagulants that lead to multi-factorial activation of factor X and subsequent thrombin generation and fibrin formation that in turn contribute to tumor growth and metastatic spread. The activity of factor Xa is inhibited by TFPI (tissue factor pathway inhibitor). Another mechanism of direct inhibition of factor Xa involves protein Z (PZ). Protein Z is a 62-kD, vitamin K-dependent plasma nonpeptidase glycoprotein, which, in complex with PZ-dependent protease inhibitor (ZPI), inhibits factor Xa in the presence of Ca2+ and phospholipids. However, data on the presence of the PZ in tumor malignant tissue are lacking. Results obtained from randomized clinical trials indicate that inhibition of blood coagulation may improve the results of anticancer therapy in selected tumor types. The purpose of the study was to evaluate the localization of PZ in situ in colon, breast, gastric, laryngeal, pancreatic, renal, endometrial cancer, non-small cell lung cancer (NSCLC), malignant melanoma and glial neoplasms. Studies were performed on tumor fragments obtained at surgical treatment of proviously untreated patients. Immunohistochemical procedures using the ABC method employed a specific polyclonal antibody directed against human PZ antigen. Protein Z was localized in cancer cell bodies in all types of malignant tumors examined. Staining intensity was more pronounced in less differentiated cancer cells of anaplastic gliomas. In contrast, more differentiated cancer cells of gastric cancer revealed stronger staining than more malignant ones. Cancer cell bodies of NSCLC and renal cancer were characterized by weak intensity of staining for PZ. In the case of pancreatic and renal cancer, as well as malignant melanoma, the intensity of staining for PZ in cancer cell bodies was irregular: both high and low expression of PZ was observed independent of the degree of malignancy. The expression of PZ was also revealed in association with tumor infiltrating macrophages in colon cancer, NSCLC and malignant melanoma. Furthermore, PZ was localized in small blood vessels of colon, renal, endometrial, gastric cancer, NSCLC, malignant melanoma and glial neoplasms. The observed localization of PZ, particularly in association with cancer cells of all malignant tumors examined, suggests that this protein may exert regulatory effects on tumor growth and metastatic dissemination.

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Gleixner, Karoline V., Mayerhofer Matthias, Anja Vales, Alexander Gruze, Michael Kneidinger, Gregor Hoermann, Maria T. Krauth et al. « Targeting of Heat Shock Protein 32 (Hsp32) in Neoplastic Cells by Styrene Maleic Acid Zinc Protoporphyrin (SMA-ZnPP) Is Associated with Reduced Growth and Induction of Apoptosis. » Blood 108, n^o 11 (16 novembre 2006) : 4323. http://dx.doi.org/10.1182/blood.v108.11.4323.4323.

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Abstract Heat shock protein 32 (Hsp32), also known as heme oxygenase-1 (HO-1), is a stress-related survival factor that has recently been implicated in enhanced survival of neoplastic cells. We here show that Hsp32/HO-1 is expressed abundantly in primary neoplastic cells in various solid tumors and hematopoietic neoplasms such as acute myeloid leukemia (AML) or chronic myeloid leukemia (CML), and in respective cell lines including the AML cell lines HL60, KG1, KG1a, and U937, CML cell lines K562 and KU812, eosinophilic leukemia cell line EOL-1, mast cell leukemia cell line HMC-1, myeloma cell lines RPMI8226 and U266, breast cancer cell line MDA MB 231, lung cancer cell line A549, pancreatic carcinoma cell line BxPC-3, colon carcinoma cell lines COLO201, COLO205, COLO320DM, and DLD-1, and the ovarian carcinoma cell line OVCAR-3. Expression of Hsp32 mRNA was demonstrable by RT-PCR and Northern blotting, and expression of the Hsp32 protein by Western blotting and immunocytochemistry. The CML-specific oncoprotein BCR/ABL and the transforming oncoprotein KIT D816V that is expressed in neoplastic mast cells, were found to promote expression of Hsp32 in Ba/F3 cells. In order to examine the functional role of Hsp32 in neoplastic cells, a specific siRNA was employed. Expression of Hsp32 siRNA resulted in reduced viability and induction of apoptosis in all cell lines tested. To further explore the value of Hsp32 as a target in neoplastic cells, a novel specific Hsp32-targeting compound, styrene maleic acid copolymer zinc protoporphyrin micelles (SMA-ZnPP) was applied. Exposure to SMA-ZnPP resulted in a significant decrease in proliferation determined by 3H-thymidine uptake, in all cell lines as well as in all primary neoplastic cells tested (AML, n=5; CML, n=5; mastocytosis, n=3; breast cancer, n=2; lung cancer, n=1). As assessed by AnnexinV-staining, Tunel assay and electron microscopy, the growth-inhibitory effects of SMA-ZnPP were found to be associated with induction of apoptosis. In each cell type, the effect of SMA-ZnPP on growth was dose-dependent and found to occur at pharmacologic concentrations (IC50 1–30 μM). Moreover, SMA-ZnPP was found to synergize with various anti-neoplastic drugs (tumor cell lines: cisplatin, leukemias: cytarabine, myeloma: bortezomib) in producing growth inhibition. In summary, these data show that Hsp32/HO-1 is an important survival factor and novel interesting target in various hematopoietic and non-hematopoietic neoplasms. Based on these data, it seems desirable to explore the value of the Hsp32-targeting drug SMA-ZnPP in clinical trials in patients with leukemias and solid tumors.

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Gleixner, K. V., M. Mayerhofer, A. Vales, A. Gruze, W. F. Pickl, E. Lackner, C. Sillaber, C. C. Zielinski, H. Maeda et P. Valent. « The Hsp32/HO-1-targeted drug SMA-ZnPP counteracts the proliferation and viability of neoplastic cells in solid tumors and hematologic neoplasms ». Journal of Clinical Oncology 25, n^o 18_suppl (20 juin 2007) : 14122. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14122.

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14122 Background: Heat shock protein 32 (Hsp32) is a stress-related survival factor that is overexpressed in various neoplastic cells. Recently, specific Hsp32- targeting drugs such as styrene maleic acid encapsulated zinc protoporphyrin (SMA-ZnPP) have been developed. Methods: We examined the effects of SMA-ZnPP on proliferation and survival of various tumor cell-lines, including U97MG (glioblastoma), A549 (lung cancer), MDA-MB-231 (breast cancer), BxPC-3 (pancreatic), HepG2 (hepatocellular), Colo201, Colo320DM, DLD-1 (colon), OvCar3 (ovarian carcinoma), KG1, U937, HL60, K562 (myeloid leukemias), RAJI, NALM-6 (lymphatic leukemias), RPMI 8226, U266 (multiple myeloma) as well as on primary neoplastic cells. Moreover, Ba/F3 cells with doxycycline-inducible expression of oncoproteins (RAS-G12V, BCR/ABL, KIT-D816V) were analyzed. Expression of Hsp32 mRNA was examined by RT-PCR and Northern blotting, and expression of the Hsp32 protein by Western blotting. To silence Hsp32 in neoplastic cells, we used specific siRNA as well as SMA-ZnPP. Proliferation was analyzed by 3H-thymidine uptake and apoptosis by light microscopy. Results: All neoplastic cells tested were found to express Hsp32 mRNA and the Hsp32 protein in a constitutive manner. In Ba/F3 cells, induction of RAS-G12V, BCR/ABL, or KIT D816V enhanced the expression of Hsp32. The Hsp32 siRNA was found to lead to a reduced viability and induction of apoptosis. Treatment of malignant cells with SMA-ZnPP resulted in a significant decrease in proliferation and induction of apoptosis. The effects of SMA- ZnPP on primary neoplastic cells and cell lines were dose-dependent and occurred at pharmacologic concentrations (IC50 1–30 μM). Moreover, SMA-ZnPP was found to synergize with various anti-neoplastic drugs (cisplatin, cytarabine, tyrosine kinase inhibitors, bortezomib) in producing growth-inhibition in neoplastic cells. Conclusions: The Hsp32-targeting drug SMA-ZnPP counteracts malignant cell growth and sensitizes neoplastic cells against various other targeted or conventional antineoplastic drugs. Hsp32-targeting drugs may represent an interesting new aproach to inhibit malignant cell growth in solid tumors and leukemias. No significant financial relationships to disclose.

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Morrison, A. A., J. P. Venables, G. Dellaire et M. R. Ladomery. « The Wilms tumour suppressor protein WT1 (+KTS isoform) binds alpha-actinin 1 mRNA via its zinc-finger domain ». Biochemistry and Cell Biology 84, n^o 5 (octobre 2006) : 789–98. http://dx.doi.org/10.1139/o06-065.

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Mutations in WT1 are associated with developmental syndromes that affect the urogenital system and neoplasms, including Wilms tumour, acute myeloid leukemia, and breast and prostate cancers. The WT1 protein belongs to the early growth response family of zinc-finger transcription factors. Uniquely to WT1, an evolutionarily conserved alternative splice event inserts the tripeptide KTS, between zinc fingers 3 and 4. Whereas –KTS isoforms bind DNA and activate or repress transcription, +KTS isoforms bind DNA less efficiently and interact with splice factors and RNA in vitro and in vivo. Although candidate DNA targets have been found, physiological mRNA targets are yet to be defined. We examined the distribution of WT1 in ribonucleoprotein (RNP) complexes in nuclear extract prepared from M15 cells, a mouse mesonephric fetal kidney cell line. WT1 cofractionated with the splice factor PSF in large RNP particles ≥2 MDa. We also found that PSF co-immunoprecipitated with WT1, suggesting a functional interaction between these 2 multifunctional proteins. Using yeast three-hybrid library constructed from the co-immunoprecipitated RNA we found that WT1 (+KTS) binds close to or at the start codon of alpha-actinin 1 (ACTN1) mRNA. A band shift assay confirmed the ability of the WT1 zinc-finger domain (+KTS) to bind this sequence in vitro. ACTN1 is the first likely physiological mRNA target of WT1.

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Seregni, E., C. Botti, G. Grasselli et E. Bombardieri. « Biochemical characteristics and biological profile of prostate specific antigen (PSA) ». Urologia Journal 62, n^o 3 (juin 1995) : 402–8. http://dx.doi.org/10.1177/039156039506200319.

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Since its identification in seminai fluid in 1971, a tot more knowledge has been obtained about the biology and expression of prostate specific antigen (PSA). PSA is a glycoprotein consisting of 93% aminoacids and 7% carbohydrates with a molecular weight of about 30000 dalton. Functionally and structurally PSA is a kallikrein-like serine protease and its physiological role is the degradation of the major proteins of the seminal coagulum (semenogelin I and II, fibronectin) leading to semen liquefaction. The PSA gene is located on the 13q region of chromosome 19 and has a high degree of homology (more than 80%) with the gene of human glandular kallikrein (hGK1). PSA production and expression are preferentially but not exclusively associated with the normal, benign hyperplastic and cancerous tissues of the prostate. In fact, it has been demonstrated that PSA is also present in the accessory male sex glands of Cowper, Littre and Morgagni and other extra-prostatic neoplasms, such as salivary gland tumours and breast cancer. Many factors may influence PSA synthesis and production and among them the most important are androgen and growth factor stimulation. Advances have recently been made on the molecular isoforms of PSA. In the seminai fluid PSA seems partially bound to a serpine (protein C inhibitor), whilst in the serum PSA is predominantly associated to α-antichymotrypsin (ACT) and in low quantity to α2-macroglobulin (α2M). All these findings will have implications on clinical applications of PSA as a tumour marker for prostate cancer.

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Clines, G. A., et T. A. Guise. « Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone ». Endocrine-Related Cancer 12, n^o 3 (septembre 2005) : 549–83. http://dx.doi.org/10.1677/erc.1.00543.

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Calcium homeostasis is a tightly regulated process involving the co-ordinated efforts of the skeleton, kidney, parathyroid glands and intestine. Neoplasms can alter this homeostasis indirectly through the production of endocrine factors resulting in humoral hypercalcaemia of malignancy. Relatively common with breast and lung cancer, this paraneoplastic condition is most often due to tumour production of parathyroid hormone-related protein and ensuing increased osteoclastic bone resorption. Although control of hypercalcaemia is generally successful, the development of this complication is associated with a poor prognosis. The metastasis of tumour cells to bone represents another skeletal complication of malignancy. As explained in the ‘seed and soil’ hypothesis, bone represents a fertile ground for cancer cells to flourish. The molecular mechanisms of this mutually beneficial relationship between bone and cancer cells are beginning to be understood. In the case of osteolytic bone disease, tumour-produced parathyroid hormone-related protein stimulates osteoclasts that in turn secrete tumour-activating transforming growth factor-β that further stimulates local cancer cells. This ‘vicious cycle’ of bone metastases represents reciprocal bone/cancer cellular signals that likely modulate osteoblastic bone metastatic lesions as well. The development of targeted therapies to either block initial cancer cell chemotaxis, invasion and adhesion or to break the ‘vicious cycle’ is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.

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Sierko, Ewa, Marek Wojtukiewicz, Piotr Tokajuk, Lech Zimnoch, Rodryg Ramlau, Walter Kisiel et George J. Broze. « Expression of Protein Z (PZ) and Protein Z-Dependent Protease Inhibitor (ZPI) In Situ in Human Malignant Tissues. » Blood 106, n^o 11 (16 novembre 2005) : 1028. http://dx.doi.org/10.1182/blood.v106.11.1028.1028.

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Abstract The activity of the hemostatic system components facilitates tumor growth and dissemination. There exists a mechanism of direct inhibition of factor Xa that involves protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) system. ZPI also attenuates the activity of factor XIa. Data on the presence of PZ and ZPI in malignant tissue in situ are lacking. The aim of this study was to assess the localization of PZ and ZPI in situ in colon, breast, gastric, laryngeal, pancreatic, renal, endometrial cancer, non-small cell lung cancer (NSCLC), malignant melanoma and glial neoplasms. Studies were performed on tumor tissues obtained at surgical treatment of previously untreated patients. Immunohistochemical procedures according to the ABC method and Envision Double Staining System (Dako) employed a polyclonal antibody against PZ and a monoclonal antibody against ZPI. Protein Z was localized in cancer cell bodies in all types of malignant tumors examined. Staining intensity was more pronounced in less differentiated cancer cells of anaplastic gliomas. In contrast, more differentiated cancer cells of gastric cancer revealed stronger staining than less malignant ones. Cancer cell bodies of NSCLC and renal cancer were characterized by weak intensity of staining for PZ. In pancreatic and renal cancer, as well as in malignant melanoma, the intensity of staining for PZ in cancer cells was irregular: both high and low PZ expression was observed independently of the degree of malignancy. Protein Z was also revealed in association with macrophages in colon cancer, NSCLC and malignant melanoma. Expression of ZPI was observed in cancer cell bodies in all examined specimens. The staining intensity for ZPI was irregular: both strong and weak expression of ZPI was observed. Various percentages of ZPI-positive cancer cells were observed in different specimens of the tissues examined. In colon cancer, ZPI expression was detected in tumor infiltrating macrophages. Double staining studies revealed co-expression of both proteins in cancer cell bodies in all examined tumor types, although there were areas of tumor foci where only one protein (either ZP or ZPI) was localized. Our results suggest that PZ and ZPI, apart from being inhibitors of blood coagulation, may play an additional regulatory role in tumor progression.

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Yoshimi, Akihide, Zhaoqi Liu, Wang Jiguang, Hana Cho, Stanley C. Lee, Michelle Ki, Lillian E. Bitner et al. « Mutations in the RNA Splicing Factor SF3B1 Promote Transformation through MYC Stabilization ». Blood 132, Supplement 1 (29 novembre 2018) : 882. http://dx.doi.org/10.1182/blood-2018-99-110328.

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Abstract Mutations in the RNA splicing factor SF3B1 are recurrent in CLL and myeloid neoplasms but their functional role in promoting tumorigenesis remain poorly understood. While SF3B1 mutations have been identified as promoting use of aberrant 3' splice sites (3'ss), consistent identification of mis-spliced transcripts and pathways that functionally link mutant SF3B1 to transformation remains elusive. Moreover, large-scale analyses of the impact of mutant SF3B1 on gene expression and gene regulatory networks, which may be distinct from aberrant splicing changes, remain to be performed. We therefore sought to elucidate the effects of SF3B1 mutations across hematopoietic malignancies and cancer lineages at the level of both mRNA splicing and expression. To this end, we collected RNA-seq data from 79 tumors and 12 isogenic cell lines harboring SF3B1 hotspot mutations. The most frequent hotspot, K700E, was the most common mutation in CLL and breast cancers while mutations at position R625 were restricted to melanomas (Figure A, B). Regulatory network analysis of differentially expressed genes in SF3B1 mutated CLL identified MYC as the top master regulator (Figure C). MYC activation in SF3B1 mutated CLL was also verified by differential expression analyses (Figure D) and was common to SF3B1K700E mutant cancers while absent in cancers with mutations affecting R625. Taken together, these observations suggested that tumors harboring SF3B1K700E mutations activate the MYC transcriptional program. We next sought to verify the effects of c-Myc activation by mutant Sf3b1 in the B-cell lineage in vivo. We crossed Cd19-cre Sf3b1K700E/+ mice with Eμ-Myc transgenic mice to generate Cd19-cre+ control, Sf3b1K700E/+, Eμ-MycTg/+, and Sf3b1K700E/+Eμ-MycTg/+ double-mutant mice. While control or single mutant primary mice did not develop disease over one year, double-mutant mice developed a lethal B-cell malignancy. This effect was consistent in serial transplantation, where mice transplanted with double-mutant cells had shorter survival compared to single-mutant controls (Figure E). These data provide the first evidence that SF3B1 mutations contribute to tumorigenesis in vivo. To understand the molecular mechanism for MYC activation across SF3B1 mutant human and mouse cells, we analyzed RNA-seq data from CLL patients, isogenic Nalm-6 cells, and splenic B-cells from the mouse models. This revealed a significant overlap in aberrant (3'ss) events across SF3B1 mutant samples. Interestingly, mis-spliced events across mouse and human SF3B1K700E mutant samples identified aberrant 3'ss usage and decay of PPP2R5A (Figure F), a gene whose product has previously been shown to regulate c-MYC protein stability and the only gene whose aberrant splicing was most prominent in K700E compared with R625 mutant SF3B1. PPP2R5A is a subunit of the PP2A phosphatase complex that dephosphorylates Serine 62 (S62) of c-MYC, resulting in an unstable form of c-MYC that is a substrate for proteasomal degradation. Consistent with this, SF3B1K700E mutant cells exhibited dramatic increase in S62-phosphorylated c-MYC and increased stability of c-MYC protein. MYC expression, stability, and S62 phosphorylation could be abrogated in SF3B1 mutant cells by restoring PPP25RA expression. In addition to c-MYC S62 phosphorylation, PPP2R5A-containing PP2A reduced S70 phosphorylation of BCL2 (a modification important for apoptosis induction) in SF3B1 mutant cells. To functionally evaluate the importance of impaired PP2A enzymatic activity in SF3B1 mutant cells further, we assessed the therapeutic potential of the FDA-approved oral PP2A activator, FTY-720. SF3B1 mutant cells were more sensitive to FTY-720 treatment than SF3B1 WT counterparts, experiencing growth arrest at lower concentration (Figure G). Moreover, both S62-phosphorylated c-MYC and S70-phosphorylated BCL2 decreased in a dose-dependent manner upon treatment with FTY-720 (Figure H). Here through combined evaluation of the effects of the SF3B1 mutation on splicing, gene expression, and transcriptional networks across cancer types, we identify a novel mechanism by which mutant SF3B1-mediated alterations in RNA splicing contribute to activation of oncogenic MYC through effects on MYC proteolysis. Moreover, these data highlight a novel therapeutic approach targeting the impact of mutant SF3B1 on post-translational modification of MYC. Figure. Figure. Disclosures Mato: Janssen: Consultancy, Honoraria; Celgene: Consultancy; Prime Oncology: Speakers Bureau; TG Therapeutics: Research Funding; Regeneron: Research Funding; Abbvie: Consultancy; Sunesis: Honoraria, Research Funding; Acerta: Research Funding; AstraZeneca: Consultancy; Pharmacyclics: Consultancy, Honoraria, Research Funding.

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Hugo, Zachary P., Michael C. Perry et David P. Steensma. « Extreme Leukocytosis in the 21st Century Is Often Iatrogenic ». Blood 112, n^o 11 (16 novembre 2008) : 5401. http://dx.doi.org/10.1182/blood.v112.11.5401.5401.

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Abstract Background: Most reports of the causes of extreme leukocytosis (i.e., total white blood count (WBC) >50 × 109/L) have included relatively small numbers of cases or data from the era prior to FDA approval of filgrastim (recombinant G-CSF; February 1991), sargramostim (GM-CSF; March 1991), and pegfilgrastim (G-CSF conjugated to polyethylene glycol; January 2002). The contribution of myeloid growth factors to extreme leukocytosis in contemporary medical practice is unclear. Methods: We evaluated the medical records of all patients with extreme leukocytosis evaluated in the clinical laboratory of the University of Missouri-Columbia (UMC) Medical Center during the years 2000 to 2007. We collected complete blood count data, information on the etiology of the leukocytosis, demographic factors, and clinical complications. Results: We identified 371 unique patients who had at least one WBC >50 × 109/L during this 8-year period (43.7% females; median age 56 (range 0–92)). Review of the primary cause of the leukocytosis in each case revealed that, while the various subtypes of leukemia (n=165, 44.5% of cases) and leukemoid reactions to general medical disorders (n=155, 41.8%) still represent the most common etiologies of extreme WBC elevation, growth factor-associated leukocytosis (GFL) is common, accounting for 13.7% (n=51) of patients. Among the subset of patients with GFL, the median peak WBC count was 60.8 × 109/L (range, 50–114.7); 51% were female, and the median age was 52 years (range 0–85). The median absolute WBC differential was as follows: neutrophils 40.8 × 109/L, granulocytes 55.7, bands 7.1, lymphocytes 2.4, monocytes 1.3, eosinophils 0, and basophils 0. Most (84%) of the patients receiving growth factors were being treated for cancer, the most common being non-Hodgkin lymphoma (NHL, 19.6%), Hodgkin lymphoma (HL, 11.8%), breast cancer (9.8%), ovarian cancer (5.9%), melanoma (5.9%), and endometrial cancer (5.9%). The non-malignant diagnoses (n = 8) included autoimmune neutropenia, bruton’s agammagloblinemia with pneumonia, leukopenia of undefined etiology, preterm neutropenia/sepsis (n = 4), and neutropenia associated with HIV. 70.6% of patients with GFL were receiving filgrastim, 29.4% pegfilgrastim, and 0% sargramostim. 0% of patients were undergoing conditioning for stem cell transplant. While myeloid growth factors are generally well tolerated, extreme leukocytosis is concerning because it may be associated with serious adverse events such as spontaneous splenic rupture, leukostasis/hyperviscosity, and hemorrhage. Other diagnoses continue to be important contributors to extreme leukocytosis. Of the 165 patients with leukemia, 43% were diagnosed with CLL, 15.8% CML, 15.2% AML, 13.3% ALL, 3.6% CMML, 3.6% BCR/ABL-negative myeloproliferative disorders, and 3.6% NHL. Other diagnoses included plasma cell leukemia, undifferentiated leukemia, and an undefined lymphoproliferative disease with macroglobulinemia variant. The causes of non-clonal leukocytosis (leukemoid reactions) could be divided into four broad categories: infection (n=109, 70.3%), reaction to hemorrhage (n=15, 9.7%), paraneoplastic (n=11, 7.1%), and other miscellaneous causes (20, 12.9%). The most common infections causing extreme leukocytosis include sepsis (59, 54.1%), pneumonia (19, 17.4%), and Clostridium difficile-associated colitis (5, 4.6%). Paraneoplastic causes of leukocytosis were diverse and associated neoplasms included cancer of unknown primary (n = 2), cholangiocarcinoma, extranodal marginal zone B-cell lymphoma, HL, SCLC, NSCLC, lymphoplasmacytic lymphoma, melanoma, peripheral T-cell lymphoma, and squamous cell carcinoma of the penis. Conclusion: In the current era, extreme leukocytosis is often iatrogenic and associated with filgrastim or pegfilgrastim usage. WBC counts should be routinely monitored in patients receiving pegfilgrastim or filgrastim and the medication discontinued with evolving leukocytosis.

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Kon, Ayana, Masashi Sanada, Kenichi Yoshida, Yasunobu Nagata, Yuichi Shiraishi, Yusuke Sato, Aiko Sato-Otsubo et al. « Functional Analysis of SRSF2 Mutations in Myelodysplastic Syndromes and Related Disorders ». Blood 118, n^o 21 (18 novembre 2011) : 1706. http://dx.doi.org/10.1182/blood.v118.21.1706.1706.

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Abstract Abstract 1706 The recent study of whole-exome sequencing on MDS has revealed frequent and specific pathway mutations involving multiple components of the RNA splicing machinery, including U2AF35, SRSF2, SF3B1 and ZRSR2. The mutually exclusive manner of these mutations among MDS cases also supported that deregulated RNA splicing contributes to the pathogenesis of MDS. Interestingly, the distribution of these splicing pathway mutations shows a substantial difference with regard to disease subtypes. Thus, the SF3B1 mutations are by far the most frequent in RARS and RCMD-RS cases, and the SRSF2 mutations are more prevalent in CMML. SRSF2 is a member of the SR protein family that is commonly characterized by one or two RNA recognition motifs (RRM) and a signature serine/arginine-rich domains (RS domains). The SR proteins interact with other spliceosome components through their RS domains, among which most extensively characterized are SRSF1 (ASF/SF2) and SRSF2 (SC35). Both SR proteins bind a splicing enhancer site within the 3' target exon and also interact with the U2AF, playing an indispensable role in both constitutive and alternative splicing in most cell types. In fact, the knockout of these genes in mice results in embryonic lethality. There is emerging evidence that establishes a connection between the abnormal expression of SR proteins and the development of cancer, mainly as a result of change in the alternative splicing patterns of key transcripts. Increased expression of SR proteins usually correlates with cancer progression, as shown by elevated expression of SR proteins in ovarian cancer and breast cancer. In spite of the similarity in their functions, both proteins are thought to have distinct roles, especially in the pathogenesis of myeloid malignancies, since we found no SRSF1 mutations among 582 cases with myeloid neoplasms. On the other hand, studies have shown that increased expression of SRSF1 transforms immortal rodent fibroblasts and leads to the formation of sarcomas in nude mice, supporting the notion that SRSF1 is a proto-oncogene, whereas SRSF2 does not have transforming activity, indicating a highly specific role of SRSF1 in this type of cancer. Thus, little is known about the biological mechanism by which the SRSF2 mutations are involved in the pathogenesis of MDS, although the mutations at the P95 site are predicted to cause a significant displacement of the RS domain relative to the domain for RNA binding. So to gain an insight into the functional aspect of SRSF2 mutations, we performed sequencing analysis of mRNAs extracted from mutant (P95H) SRSF2-transduced HeLa cells in which expression of the wild-type and mutant SRSF2 were induced by doxycycline. The abnormal splicing in mutant SRSF2-transduced cells was directly demonstrated by evaluating the read counts in different fractions. Next, to investigate functional role of SRSF2 mutant, HeLa cells were transduced with lentivirus constructs expressing either the P95H SRSF2 mutant or wild-type SRSF2, and cell proliferation was examined. After the induction of gene expression, the mutant SRSF2-transduced cells showed reduced cell proliferation. In addition, we transduced P95H SRSF2 constructs into factor-dependent 32D cell lines. The expression of mutant SRSF2 protein resulted in increased apoptosis in the presence of IL-3 and also suppression of cell growth in the presence of G-CSF, which may be related to ineffective hematopoiesis, a common feature of MDS. To further clarify the biological effect of SRSF2 mutants in vivo, a highly purified hematopoietic stem cell population (CD34-c-Kit+ScaI+ Lin-) prepared from C57BL/6 (B6)-Ly5.1 mouse bone marrow was retrovirally transduced with either the mutant or wild-type SRSF2 with EGFP marking. The transduced cells were mixed with whole bone marrow cells from B6-Ly5.1/5.2 F1 mice, transplanted into lethally irradiated B6-Ly5.2 recipients, and we are now monitoring the ability of these transduced cells to reconstitute the hematopoietic system and other hematological phenotypes. Much remains, however, to be unrevealed about the functional link between the abnormal splicing of RNA species and the phenotype of myelodysplasia. Further functional studies should be warranted to understand these mechanisms in detail. In this meeting, we will present the results of our functional studies on the SRSF2 mutations and discuss the pathogenesis of MDS in terms of the alterations of splicing machinery. Disclosures: No relevant conflicts of interest to declare.

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Durán, Mercedes, Iris Faull, Enrique Lastra, Jean-Francois Laes, Ana Belén Rodrigo et Ricardo Sánchez-Escribano. « ARID1A genomic alterations driving microsatellite instability through somatic MLH1 methylation with response to immunotherapy in metastatic lung adenocarcinoma : a case report ». Journal of Medical Case Reports 15, n^o 1 (19 février 2021). http://dx.doi.org/10.1186/s13256-020-02589-1.

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Abstract Background Tumor molecular screening allows categorization of molecular alterations to select the best therapeutic strategy. AT-rich interactive domain-containing 1A (ARID1A) gene mutations are present in gastric, endometrial, and clear cell ovarian tumors. Inactivation of this gene impairs mismatch repair (MMR) machinery leading to an increased mutation burden that correlates with microsatellite instability (MSI), associated with tumor-infiltrating lymphocytes and programmed death ligand 1 (PD-L1) expression. This is the first case report in lung adenocarcinoma of ARID1A gene alterations leading to sporadic MSI, through somatic mutL homolog 1 (MLH1) promoter methylation, with an MLH1 gene mutation as the second somatic hit. Case presentation A 50-year-old never-smoker Bulgarian woman, with no comorbidities and no family history of cancer, was diagnosed with metastatic lung adenocarcinoma. PD-L1 immunohistochemistry (IHC) of tissue biopsies on right groin adenopathies resulted in 30% positivity. Liquid biopsy test reported actionable alterations in ARID1A gene, rearranged during transfection (RET) gene fusions, epidermal growth factor receptor (EGFR) gene R776H mutation, breast cancer (BRCA) genes 1/2, and cyclin-dependent kinase inhibitor 2A (CDKN2A) gene mutations. The patient was treated with immunotherapy, and showed a treatment response lasting for 19 months until a new metastasis appeared at the right deltoid muscle. Genomic analysis of a sample of this metastasis confirmed PD-L1 positivity of greater than 50% with CD8+ T cells expression and showed MSI with a deleterious c.298C>T (p.R100*) MLH1 gene mutation. Multiplex ligation-dependent probe amplification (MLPA) of this sample unveiled MLH1 gene promoter methylation. The MLH1 gene mutation and the MLH1 gene methylation were not present at the germline setting. Conclusions In this particular case, we show that ARID1A gene mutations with sporadic MSI due to somatic MLH1 gene promoter methylation and MLH1 gene mutation could change the prognosis and define the response to immunotherapy in a patient with lung adenocarcinoma. Comprehensive solid and liquid biopsy tests are useful to find out resistance mechanisms to immune checkpoint inhibitors. Our data encourages the development of new therapies against ARID1A mutations and epigenomic methylation when involved in MSI neoplasms.

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Radford, Diane M., Jame Abraham et Stephen R. Grobmyer. « Triple-Negative Breast Cancer ». DeckerMed CGSO Case-Based Reviews, 14 février 2019. http://dx.doi.org/10.2310/cgso.16011.

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Triple-negative breast cancers (TNBCs), negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, account for 15 to 20% of all female breast cancers. TNBC is heterogeneous based on gene expression microarray, and identification of TNBC subtypes and their behavior has the potential to enable more targeted, neoadjuvant, and adjuvant interventions. TNBCs usually are higher grade (Nottingham score 3) and are more common in younger, Hispanic, and African American women. They are more aggressive, have an increased likelihood of distant disease and mortality, are larger at presentation, and are more likely to be associated with lymph node metastases. Patients with TNBC are at a higher risk for visceral metastases early in the course of the disease. Genetic risk evaluation is recommended for patients with TNBC diagnosed at or before 60 years of age. Surgical management may be influenced by gene testing results. Standard adjuvant chemotherapy is anthracycline or taxane based. This review contains 5 figures, 8 tables, and 51 references. Key Words: adjuvant, BRCA, chemotherapy, hormone receptor negative, neoadjuvant, genetics, triple-negative breast cancer, breast neoplasm.

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Radford, Diane M., Jame Abraham et Stephen R. Grobmyer. « Triple-Negative Breast Cancer ». DeckerMed Complex General Surgical Oncology, 14 février 2019. http://dx.doi.org/10.2310/7800.16011.

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Triple-negative breast cancers (TNBCs), negative for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2, account for 15 to 20% of all female breast cancers. TNBC is heterogeneous based on gene expression microarray, and identification of TNBC subtypes and their behavior has the potential to enable more targeted, neoadjuvant, and adjuvant interventions. TNBCs usually are higher grade (Nottingham score 3) and are more common in younger, Hispanic, and African American women. They are more aggressive, have an increased likelihood of distant disease and mortality, are larger at presentation, and are more likely to be associated with lymph node metastases. Patients with TNBC are at a higher risk for visceral metastases early in the course of the disease. Genetic risk evaluation is recommended for patients with TNBC diagnosed at or before 60 years of age. Surgical management may be influenced by gene testing results. Standard adjuvant chemotherapy is anthracycline or taxane based. This review contains 5 figures, 8 tables, and 51 references. Key Words: adjuvant, BRCA, chemotherapy, hormone receptor negative, neoadjuvant, genetics, triple-negative breast cancer, breast neoplasm.

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« Expression of stem cell growth factor receptor CD117 (C-Kit) in breast neoplasms ». IP Journal of Diagnostic Pathology and Oncology 3, n^o 2 (15 juin 2018) : 55–59. http://dx.doi.org/10.18231/2581-3706.2018.0014.

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Dugăeșescu, Monica, Florentina Mușat et Octavian Andronic. « The Polymorphisms of Epidermal Growth Factor-driven Signaling and Cancer Pathogenesis ». Sudan Journal of Medical Sciences, 30 juin 2021. http://dx.doi.org/10.18502/sjms.v16i2.9289.

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Background: Epidermal growth factor (EGF) is a stimulating protein for cell proliferation and differentiation. An amplification of its signaling pathway has been frequently reported in numerous malignant tumors. Specific polymorphisms of the genes encoding proteins involved in this cellular pathway may constitute risk factors for carcinogenesis. The aim of this study was to identify the most relevant polymorphisms of EGF and their signaling pathways and their relation to carcinogenesis. Methods: The study included 40 full-text articles published between January 2010 and May 2020, extracted from PubMed, Scopus, Web of Science, and Science Direct databases in May 2020, using the following keywords: EGF OR epidermal growth factor AND polymorphism AND cancer OR neoplasia OR tumor. Results: We identified relevant polymorphisms of the EGF signaling pathway that were involved in the development and progression of hepatocellular carcinoma, esophageal cancer, gastric cancer, colorectal cancer, glioma, lung cancer, breast cancer, cervical cancer, and head and neck cancer. Rs4444903 variants have been widely studied and the association with numerous tumors has been confirmed by multiple studies. Other frequently investigated polymorphisms are –191C/A and –216G>T. Conclusion: The polymorphisms of EGF signaling pathway have been widely studied in connection to various malignancies. Some predisposing variants are common in different forms of cancer. These polymorphisms might be general risk factors for carcinogenesis.

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Xu, Fangfang, Hui Li et Chengjiu Hu. « LIFR-AS1 modulates Sufu to inhibit cell proliferation and migration by miR-197-3p in breast cancer ». Bioscience Reports 39, n^o 7 (juillet 2019). http://dx.doi.org/10.1042/bsr20180551.

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AbstractNumerous evidence has recently demonstrated that long non-coding RNAs (lncRNAs) play vital roles in the oncogenesis and development of a wide range of human neoplasms. Leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1), a novel cancer-related lncRNA, has been reported to be under-expressed in breast cancer and associated with poor prognosis. However, the exact role of LIFR-AS1 in breast cancer remains largely unclear. The present study aimed to investigate the biological role of LIFR-AS1 in breast cancer and clarify the potential molecular mechanisms. In the present study, we found that LIFR-AS1 was significantly down-regulated in both tissues and cell lines. Furthermore, over-expression of LIFR-AS1 inhibited breast cancer cell proliferation, colony formation, migration and invasion, whereas knockdown of LIFR-AS1 promoted breast cancer cell proliferation, colony formation, migration and invasion. Moreover, LIFR-AS1 was observed to up-regulate suppressor of fused gene (Sufu) expression by competitively binding to miR-197-3p in breast cancer cells. Notably, miR-197-3p inhibitor reversed the promoting effects of LIFR-AS1 knockdown on breast cancer cell proliferation, colony formation, migration and invasion. Additionally, LIFR-AS1 knockdown promoted tumor growth in vivo. To sum up, our results imply the tumor-suppressing role of LIFR-AS1 in breast cancer.

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Di Loreto, C., FM Reis, P. Cataldi, C. Zuiani, S. Luisi, CA Beltrami et F. Petraglia. « Human mammary gland and breast carcinoma contain immunoreactive inhibin/activin subunits : evidence for a secretion into cystic fluid ». European Journal of Endocrinology, 1 août 1999, 190–94. http://dx.doi.org/10.1530/eje.0.1410190.

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OBJECTIVE: Inhibins and activins are members of the transforming growth factor beta superfamily and are known to modulate the growth and differentiation of several cell types. The present study investigated the localization of inhibin and activin subunits in human normal and pathological breast tissues. DESIGN: A cross-sectional study comparing the expression of inhibin/activin subunits alpha, betaA and betaB in surgical specimens from women undergoing reductive mammoplasty (classified, according to the phase of the menstrual cycle, as follicular, luteal, or postmenopausal), and patients submitted to lumpectomy for fibrocystic disease, benign (intraductal papilloma, adenomyoepithelioma, and hamartoma) or malignant breast neoplams (intraductal, intralobular, and invasive carcinoma). METHODS: Immunohistochemistry was used to localize inhibin alpha and activin betaA and betaB subunits in the cytoplasm of epithelial cells of mammary glands. Dimeric activin A, inhibin A and inhibin B were measured by specific two-site enzyme immunoassay in the cystic fluid collected from patients with fibrocystic disease. RESULTS: An intense staining for the alpha inhibin subunit and a mild staining for betaA and betaB subunits were present in samples obtained from normal breast tissue regardless of menstrual cycle phase, and in fibrocystic disease and benign neoplasms. Carcinoma cells stained weakly to moderately for alpha subunit and were negative for betaA and betaB subunits. Fibrocystic disease was associated with absence of betaA subunit expression in normal epithelial cells and intense staining for all subunits in the apocrine cells. Immunoreactive inhibin A, inhibin B, and activin A were also present in cystic fluid, suggesting a local secretion of these proteins. CONCLUSION: These data suggest a local expression and secretion of inhibin and activin in human normal, fibrocystic disease and neoplastic breast tissues. The low expression of these proteins may facilitate abnormal cell proliferation in breast carcinoma.

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« Iron in the Promotion and Initiation of Cancer How Free Iron Accelerates Predisposing Insulin Resistance ». Advances in Hematology and Oncology Research 1, n^o 1 (15 novembre 2018). http://dx.doi.org/10.33140/ahor.01.01.01.

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Iron is physiologically essential to life, but biochemically it is harmful because of its evident -but unappreciated- oxidative and inflammatory tissue power when it accumulates, is dosed in excess, or is free; and that because, after entering the body, unlike any other metal, its elimination is almost non-existent in man; thus, metal is a powerful promoter of chronic degenerative diseases, from diabetes, neurodegeneration to cancer, through extensive coronary and cardio-cerebrovascular disease; modifying its clinical expressivity and accelerating its severity. Iron is a powerful oxidizing and inflammatory agent, and its accumulation causes and promotes the proliferation of cancer cells in particular, both in animals and in humans. Free and accumulated iron triggers a powerful uncontrolled Cell Proliferation, permanently feeding the survival of the neoplastic cell. After more than 50 years of experimental and preclinical studies, it is clearly demonstrating the carcinogenicity of iron; and this is also proven in humans, from breast cancer and endometrium, in women, to cancer of the colon-rectum, prostate, and pancreas in men. In Western men and women, the reductions in iron deposits have an important anti-tumor and preventive effect for the development of cancer or diabetes, two entities biologically interrelated by the states of Resistance to Insulin, an inflammatory state that favors the development of malignant neoplasms, and can accelerate its aggressiveness. It is the chronic excess of insulin or its Tissue Resistance, the biological event and the clinical syndrome that increases the cancerous power of excess iron, both silent epidemics in modern man. Moderate increases in body iron levels increase the risk of acquiring cancer, and raise the level of their mortality. And its deficiency or chelation in vivo decreases the Tumor growth (Wang F, Elliott RL, Head JF: Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma Anticancer Res. 1999 Jan-Feb; 19 (1A): 445-50). If excess iron mediates and increases the risk of cancer associated with Insulin resistance, any subject with this syndrome can minimize any associated health risks (and their increased risk of cancer), avoiding iron-rich diets and donating blood with regularity; Iron is the metal that causes “exponential” and punctual mutations and fusion of genes through chromosomal translocations, constituting the greatest risk factor for human carcinogenesis. Iron is physiologically essential for life but biochemically dangerous. Chronic accumulation of iron causes pantropic organ damage and excess body iron play an important role in carcinogenesis, coronary artery disease, neurodegenerative disease, stroke and inflammatory disorders. Iron is very slowly excreted from humans once it is absorbed into the body. The significance of iron excess has been markedly underestimated, despite the fact that iron overloading disorders are as common place in the US white population. Iron-overload and catalytic iron promotes activation of oxidative responsive transcription factors and pro-inflammatory cytokines that increase cancer extension and aggravate them. There is accumulative evidence for iron as a carcinogenic metal in epidemiological, clinical, animal, and cell culture studies. The role of iron in various cancers, such as colorectal and liver cancer was demonstrated. Recent advancements on the molecular mechanisms of iron carcinogenesis evolved the Insulin-resistance generation and promotion, fisiopatologic condition that is not only permissive, but may be generated cancer and promoting it. Unlike other nutritional metals, iron is highly conserved: toxicity due to excess iron can occur either acutely after a single dose or chronically due to excessive accumulation in the body from diet. In vivo studies have demonstrated that an iron deficiency induced by either feeding a low iron diet injecting the iron chelator deferoxamine mesylate decreases tumor growth (Wang F, Elliott RL, Head JF: Inhibitory effect of deferoxamine mesylate and low iron diet on the 13762NF rat mammary adenocarcinoma Anticancer Res. 1999 Jan-Feb;19(1A):445-50). Iron supplementation has at times proven ineffective and even detrimental to health. Thus, iron excess may mediate the increased cancer risk associated with insulin resistance and heme-rich diets, and subjects who are insulin resistant can minimize any health risk associated with iron overload by avoiding heme-rich flesh foods and donating blood regularly. The energy that sustains cancer cells derived preferentially from glycolysis depends on the gene p53 deficiency-iron induced. This nutrient is postulated to contribute to the initiation of cancer in vivo, but iron overload initiates and sustain cancer development if chronic infection or insulin resistance conditions are present. Cancer cells require considerably more iron than normal cells. Since iron catalytic can induce driver point mutation and create fusion genes through chromosomal translocations, iron overload is one of the most important risk factors in human carcinogenesis. Because free iron may play a catalytic role in “spontaneous” mutagenesis, moderately elevated iron stores increased overall risk for cáncer.

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