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1
Andrikopoulou, Angeliki, Almog Shalit, Eleni Zografos, Konstantinos Koutsoukos, Anna-Maria Korakiti, Michalis Liontos, Meletios-Athanasios Dimopoulos, and Flora Zagouri. "MicroRNAs as Potential Predictors of Response to CDK4/6 Inhibitor Treatment." Cancers 13, no. 16 (August 16, 2021): 4114. http://dx.doi.org/10.3390/cancers13164114.
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Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors have emerged as novel treatment options in the management of advanced or metastatic breast cancer. MicroRNAs are endogenous non-coding 19–22-nucleotide-long RNAs that regulate gene expression in development and tumorigenesis. Herein, we systematically review all microRNAs associated with response to CDK4/6 inhibitors in solid tumors and hematological malignancies. Eligible articles were identified by a search of the MEDLINE and ClinicalTrials.gov databases for the period up to1 January 2021; the algorithm consisted of a predefined combination of the words “microRNAs”, “cancer” and “CDK 4/6 inhibitors”. Overall, 15 studies were retrieved. Six microRNAs (miR-126, miR-326, miR3613-3p, miR-29b-3p, miR-497 and miR-17-92) were associated with sensitivity to CDK4/6 inhibitors. Conversely, six microRNAs (miR-193b, miR-432-5p, miR-200a, miR-223, Let-7a and miR-21) conferred resistance to treatment with CDK4/6 inhibitors. An additional number of microRNAs (miR-124a, miR9, miR200b and miR-106b) were shown to mediate cellular response to CDK4/6 inhibitors without affecting sensitivity to treatment. Collectively, our review provides evidence that microRNAs could serve as predictive biomarkers for treatment with CDK4/6 inhibitors. Moreover, microRNA-targeted therapy could potentially maximize sensitivity to CDK4/6 inhibition.
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Kalniete, Dagnija, Miki Nakazawa-Miklasevica, Ilze Strumfa, Arnis Abolins, Arvids Irmejs, Genadijs Trofimovics, Janis Gardovskis, and Edvins Miklasevics. "MicroRNA Expression in Different Sybtypes of Breast Cancer." Acta Chirurgica Latviensis 13, no. 1 (December 1, 2013): 7–12. http://dx.doi.org/10.2478/chilat-2013-0002.
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Summary Introduction. MicroRNAs are a class of small, non-coding RNA molecules able to regulate gene expression at the post-transcriptional level through binding to the 3’-UTR of the targeted mRNA, thus suppressing translation of the mRNA. In various diseases, including malignancies, expression of microRNAs is altered. Moreover, the altered expression of the microRNAs correlates with clinical and pathophysiological features of cancer thus making them good candidates for prognostic/predictive markers. Aim of the study. The aim of this study was to determine expression level of five different microRNAs (miR-10b, miR-21, miR-29a, miR-31, and miR-214) in breast cancer tissues and to look for the differences in microRNA expression between distinct subtypes of breast cancer. Material and methods. Forty five breast cancer and corresponding resection line tissues (control tissues) were studied. Breast cancer tissues were classified into the subtypes of triple-negative (23), luminal-A (13), luminal-B (7), and HER2+ (2). Quantitative analysis of miR-10b, miR-21, miR-29a, miR-31, and miR-214 was performed by real-time PCR. The expression levels of microRNAs were normalized by the expression of the reference gene RNU6B. The event-free survival in regard of high and low expression levels of microRNAs were analyzed by Log-rank (Mantel Cox) and Gehan-Breslow-Wilcoxon tests. Results. Expression levels of four microRNAs (miR-21, miR-29a, miR-31, and miR-214) were significantly higher in cancer tissues than in corresponding resection line tissues. Breast cancer patients with low expression level of miR-21 showed a trend of better event-free survival than breast cancer patients with high expression level of miR-21; however, this trend did not reach statistical significance. In triple-negative tumor tissues, miR-21, miR-29a, and miR-31 showed significantly higher expression level than in luminal-A tumor tissues. Expression levels of miR-21 and miR-29a were significantly higher in triple-negative tumor tissues than in luminal-B tumor tissues. Conclusions. Breast cancer patients with high expression level of miR-21 in tumor tissues show a trend of worse event-free survival, though; this trend did not reach statistical significance. Different microRNA expression in distinct subtypes of breast cancer points to the genetic heterogeneity of breast cancer, different regulatory targets and signaling pathways
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Matamala, Nerea, María Teresa Vargas, Ricardo González-Cámpora, Rebeca Miñambres, José Ignacio Arias, Primitiva Menéndez, Eduardo Andrés-León, et al. "Tumor MicroRNA Expression Profiling Identifies Circulating MicroRNAs for Early Breast Cancer Detection." Clinical Chemistry 61, no. 8 (August 1, 2015): 1098–106. http://dx.doi.org/10.1373/clinchem.2015.238691.
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Abstract BACKGROUND The identification of novel biomarkers for early breast cancer detection would be a great advance. Because of their role in tumorigenesis and stability in body fluids, microRNAs (miRNAs) are emerging as a promising diagnostic tool. Our aim was to identify miRNAs deregulated in breast tumors and evaluate the potential of circulating miRNAs in breast cancer detection. METHODS We conducted miRNA expression profiling of 1919 human miRNAs in paraffin-embedded tissue from 122 breast tumors and 11 healthy breast tissue samples. Differential expression analysis was performed, and a microarray classifier was generated. The most relevant miRNAs were analyzed in plasma from 26 healthy individuals and 83 patients with breast cancer (36 before and 47 after treatment) and validated in 116 healthy individuals and 114 patients before treatment. RESULTS We identified a large number of miRNAs deregulated in breast cancer and generated a 25-miRNA microarray classifier that discriminated breast tumors with high diagnostic sensitivity and specificity. Ten miRNAs were selected for further investigation, of which 4 (miR-505-5p, miR-125b-5p, miR-21-5p, and miR-96-5p) were significantly overexpressed in pretreated patients with breast cancer compared with healthy individuals in 2 different series of plasma. MiR-505-5p and miR-96-5p were the most valuable biomarkers (area under the curve 0.72). Moreover, the expression levels of miR-3656, miR-505-5p, and miR-21-5p were decreased in a group of treated patients. CONCLUSIONS Circulating miRNAs reflect the presence of breast tumors. The identification of deregulated miRNAs in plasma of patients with breast cancer supports the use of circulating miRNAs as a method for early breast cancer detection.
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Adam-Artigues, Anna, Iris Garrido-Cano, Juan Antonio Carbonell-Asins, Ana Lameirinhas, Soraya Simón, Belén Ortega-Morillo, María Teresa Martínez, et al. "Identification of a Two-MicroRNA Signature in Plasma as a Novel Biomarker for Very Early Diagnosis of Breast Cancer." Cancers 13, no. 11 (June 7, 2021): 2848. http://dx.doi.org/10.3390/cancers13112848.
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The early diagnosis of breast cancer is essential to improve patients’ survival rate. In this context, microRNAs have been described as potential diagnostic biomarkers for breast cancer. Particularly, circulating microRNAs have a strong value as non-invasive biomarkers. Herein, we assessed the potential of a microRNA signature based on miR-30b-5p and miR-99a-5p levels in plasma as a diagnostic biomarker for breast cancer. This two-microRNA signature was constructed by Principal Component Analysis and its prognostic value was assessed in a discovery cohort and blindly validated in a second cohort from an independent institution. ROC curve analysis and biomarker performance parameter evaluation demonstrated that our proposed signature presents a high value as a non-invasive biomarker for very early detection of breast cancer. In addition, pathway enrichment analysis identified three of the well-known pathways involved in cancer as targets of the two microRNAs.
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Vimalraj, S., P. J. Miranda, B. Ramyakrishna, and N. Selvamurugan. "Regulation of Breast Cancer and Bone Metastasis by MicroRNAs." Disease Markers 35 (2013): 369–87. http://dx.doi.org/10.1155/2013/451248.
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Breast cancer progression including bone metastasis is a complex process involving numerous changes in gene expression and function. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that regulate gene expression by targeting protein-coding mRNAs posttranscriptionally, often affecting a number of gene targets simultaneously. Alteration in expression of miRNAs is common in human breast cancer, possessing with either oncogenic or tumor suppressive activity. The expression and the functional role of several miRNAs (miR-206, miR-31, miR-27a/b, miR-21, miR-92a, miR-205, miR-125a/b, miR-10b, miR-155, miR-146a/b, miR-335, miR-204, miR-211, miR-7, miR-22, miR-126, and miR-17) in breast cancer has been identified. In this review we summarize the experimentally validated targets of up- and downregulated miRNAs and their regulation in breast cancer and bone metastasis for diagnostic and therapeutic purposes.
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Jedlinski, Dominik J., Plamena N. Gabrovska, Stephen R. Weinstein, Robert A. Smith, and Lyn R. Griffiths. "Single Nucleotide Polymorphism in hsa-mir-196a-2 and Breast Cancer Risk: A Case Control Study." Twin Research and Human Genetics 14, no. 5 (October 1, 2011): 417–21. http://dx.doi.org/10.1375/twin.14.5.417.
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microRNAs are small, non-coding RNAs that influence gene expression on a post-transcriptional level. They participate in diverse biological pathways and may act as either tumor suppressor genes or oncogenes. As they may have an effect on thousands of target mRNAs, single-nucleotide polymorphisms in microRNA genes might have major functional consequences, because the microRNA's properties and/or maturation may change. miR-196a has been reported to be aberrantly expressed in breast cancer tissue. Additionally, the SNP rs11614913 in hsa-mir-196a-2 has been found to be associated with breast cancer risk in some studies although not in others. This study evaluated the association between rs11614913 and breast cancer risk in a Caucasian case-control cohort in Queensland, Australia. Results do not support an association of the tested hsa-mir-196a-2 polymorphism with breast cancer susceptibility in this cohort. As there is a discrepancy between our results and previous findings, it is important to assess the role of rs11614913 in breast cancer by further larger studies investigating different ethnic groups.
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Eichelser, Corinna, Dieter Flesch-Janys, Jenny Chang-Claude, Klaus Pantel, and Heidi Schwarzenbach. "Deregulated Serum Concentrations of Circulating Cell–Free MicroRNAs miR-17, miR-34a, miR-155, and miR-373 in Human Breast Cancer Development and Progression." Clinical Chemistry 59, no. 10 (October 1, 2013): 1489–96. http://dx.doi.org/10.1373/clinchem.2013.205161.
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BACKGROUND MicroRNAs (miRs) are small, noncoding RNAs that target genes involved in tumor development and progression. In the current study, we investigated the use of circulating miR concentrations as biomarkers in the serum of breast cancer patients. METHODS We analyzed serum samples from 120 patients with primary breast cancer after surgery and before chemotherapy (M0, classified into 3 subgroups of 40 patients with progesterone/estrogen-positive, HER2-positive, and triple-negative cancer), 32 patients with overt metastasis (M1), and 40 healthy women. Using quantitative TaqMan MicroRNA PCR, we measured the relative concentrations of 6 circulating microRNAs (miR-10b, -17, -34a, -93, -155, and -373) known to be relevant for tumor development and progression. The data were correlated with clinicopathologic risk factors, with particular reference to HER2 and hormone receptor status of the primary tumor and the presence of metastases. RESULTS The relative serum concentrations of circulating miR-34a [P = 0.013, area under the curve (AUC) 0.636], miR-93 (P = 0.001, AUC 0.699), and miR-373 (P = 0.0001, AUC 0.879) were significantly different between M0 breast cancer patients and healthy women, whereas miR-17 (P = 0.002, AUC 0.679) and miR-155 (P = 0.0001, AUC 0.781) were differently expressed between M0 and M1 patients. Increased concentrations of miR-373 were associated with negative HER2 status of the primary tumor (P = 0.0001). Deregulated concentrations of miR-17 (P = 0.019) and miR-34a (P = 0.029) were detected in patients with progesterone/estrogen receptor–positive and –negative status, respectively. CONCLUSIONS Our findings indicate that serum concentrations of deregulated microRNAs may be linked to a particular biology of breast carcinomas favoring progression and metastatic spread.
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Shao, Bin, Xiaoxia Wang, Lei Zhang, Deyu Li, Xiaoran Liu, Guohong Song, Huiqing Cao, Jun Zhu, and Huiping Li. "Plasma microRNAs Predict Chemoresistance in Patients With Metastatic Breast Cancer." Technology in Cancer Research & Treatment 18 (January 1, 2019): 153303381982870. http://dx.doi.org/10.1177/1533033819828709.
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Background: MicroRNAs contribute to chemotherapy response in different types of cancer. We hypothesized that plasma miRNAs are potentially associated with chemotherapy response in patients with metastatic breast cancer. Patients and Methods: Fourteen candidate microRNAs were chosen from the literature, and their plasma levels were measured by quantitative polymerase chain reaction (PCR). Forty metastatic breast cancer patients were chosen as the training groups. The potential significant microRNAs were validated in another 103 plasma samples. Results: In the training set, we identified 3 microRNAs (miR-200a, miR-210, and miR-451) as significantly dysregulated miRNAs between sensitive group (partial response (and stable disease) and resistant group (progressive disease). Then, in the validation set, miR-200a (area under the curve = 0.881, sensitivity = 94.1%, specificity = 76.7%) and miR-210 (area under the curve = 0.851, sensitivity = 88.2%, specificity = 72.1%) showed high diagnostic accuracy for distinguishing sensitive group from resistant group. Furthermore, the plasma level of miR-200a was significantly associated with the stage in surgery ( P = .035), and the high level of miR-210 expression was associated with internal organ metastasis (liver, lung, and brain; P = .024). Conclusions: Plasma miR-200a and miR-210 could be effective biomarkers for the prediction of chemotherapy resistance in metastatic breast cancer patients.
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Kalinina, Tatiana S., Vladislav V. Kononchuk, Alisa K. Yakovleva, Efim Y. Alekseenok, Sergey V. Sidorov, and Lyudmila F. Gulyaeva. "Association between Lymph Node Status and Expression Levels of Androgen Receptor, miR-185, miR-205, and miR-21 in Breast Cancer Subtypes." International Journal of Breast Cancer 2020 (April 23, 2020): 1–7. http://dx.doi.org/10.1155/2020/3259393.
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Breast cancer is the most commonly diagnosed cancer among women. Difficulties in treating breast cancer are associated with the occurrence of metastases at early stages of disease, leading to its further progression. Recent studies have shown that changes in androgen receptor (AR) and microRNAs’ expressions are associated with mammary gland carcinogenesis, in particular, with the formation of metastases. Thus, to identify novel metastatic markers, we evaluated the expression levels of AR; miR-185 and miR-205, both of which have been confirmed to target AR; and miR-21, transcription of which is regulated by AR, in breast cancer samples (n=89). Here, we show that the molecular subtypes of breast cancer differ in the expression profiles of AR and AR-associated microRNAs. In addition, the expression of AR and these microRNAs may depend on the expression of PR, ER, and HER2 receptors. Our results show that the possibility of using AR and microRNAs as markers depends on the tumor subtype: a decrease in AR expression may be the marker for the presence of lymph node metastases in patients with HER2-positive subtypes of breast cancer, and disturbance of miR-205, miR-185, and miR-21 expressions may be the marker in patients with a luminal B HER2-positive subtype. Cases with metastases in this type of breast cancer are characterized by a higher level of miR-205 and a lower level of miR-185 and miR-21 in tumor tissues compared to nonmetastatic cases. A decrease in the miR-185 level is also associated with lymph node metastasis in luminal B HER2-negative breast cancer. Thus, the expression levels of AR, miR-185, miR-205, and miR-21 can serve as markers to predict cancer spread to the lymph node in luminal B- and HER2-positive subtypes of breast cancer.
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Wu, Qian, Zuhong Lu, Hailing Li, Jiafeng Lu, Li Guo, and Qinyu Ge. "Next-Generation Sequencing of MicroRNAs for Breast Cancer Detection." Journal of Biomedicine and Biotechnology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/597145.
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It is reported that different microRNA (miRNA) profiles can be detected in the blood of cancer patients. We investigated that whether the key serum miRNAs could discriminate patients with and without breast cancer. This study was divided into three parts: (1) miRNA marker discovery using SOLiD sequencing-based miRNA profiling on cancerous and adjacent noncancerous breast tissue of one breast cancer patient; (2) marker selection and validation by real-time PCR on a small set of serum; (3) gene ontology analysis of the key miRNA target genes. Of genome-wide tissue miRNA expression analysis, five miRNAs were found to be altered more than fivefold by SOLiD sequencing (i.e., miR-29a, miR-23a, miR-23b, miR-192, and miR-21). All the five miRNAs were validated on the 20 breast cancer patients and 20 controls. miR-29a and miR-21 were significantly increased in the serum of breast cancer patients (). Gene ontology analysis of the target genes revealed enrichment for special biological process categories, that is, signal transduction, development, apoptosis, cell proliferation, and cell adhesion. SOLiD sequencing provides a promising method for cancer-related miRNA profiling. Serum miRNAs may be useful biomarkers for breast cancer detection.
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Hossain, Anwar, Macus T. Kuo, and Grady F. Saunders. "Mir-17-5p Regulates Breast Cancer Cell Proliferation by Inhibiting Translation of AIB1 mRNA." Molecular and Cellular Biology 26, no. 21 (August 28, 2006): 8191–201. http://dx.doi.org/10.1128/mcb.00242-06.
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ABSTRACT MicroRNAs are an extensive family of ∼22-nucleotide-long noncoding RNAs expressed in a wide range of eukaryotes, including humans, and they are important in development and disease. We found that microRNA Mir-17-5p has extensive complementarity to the mRNA of AIB1 (named for “amplified in breast cancer 1”). Cell culture experiments showed that AIB1 expression was downregulated by Mir-17-5p, primarily through translational inhibition. Expression of Mir-17-5p was low in breast cancer cell lines. We also found that downregulation of AIB1 by Mir-17-5p resulted in decreased estrogen receptor-mediated, as well as estrogen receptor-independent, gene expression and decreased proliferation of breast cancer cells. Mir-17-5p also completely abrogated the insulin-like growth factor 1-mediated, anchorage-independent growth of breast cancer cells. Our results reveal that Mir-17-5p has a role as a tumor suppressor in breast cancer cells.
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Makarova, J. A., and A. A. Poloznikov. "Intronic miRNAs of Apoptosis Genes as Indicators of Cell Death." Biotekhnologiya 35, no. 6 (2019): 108–13. http://dx.doi.org/10.21519/0234-2758-2019-35-6-108-113.
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A method to assess the apoptosis level in cell models based on the analysis of the expression of micRNAs located in introns of apoptosis genes has been developed. Bioinformation analysis identified 536 genes associated with apoptosis; 30 of them contained 38 pre-microRNAs encoding 41 mature microRNAs. A significant change in the expression of hsa-miR-1244 and hsa-miR-4479 in response to apoptosis induction in the MCF-7 breast cancer cell line was revealed. A correlation was also found between the expression level of these miRNAs and the size of the primary tumor (process stage) in patients with breast cancer. apoptosis, microRNA, MCF7, breast cancer This work was supported by the Ministry of Education and Science of the Russian Federation (Project no. RFMEFI61618X0092).
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Souza, Karen C. B., Adriane F. Evangelista, Letícia F. Leal, Cristiano P. Souza, René A. Vieira, Rhafaela L. Causin, A. C. Neuber, et al. "Identification of Cell-Free Circulating MicroRNAs for the Detection of Early Breast Cancer and Molecular Subtyping." Journal of Oncology 2019 (August 8, 2019): 1–11. http://dx.doi.org/10.1155/2019/8393769.
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Early detection is crucial for achieving a reduction in breast cancer mortality. Analysis of circulating cell-free microRNAs present in the serum of cancer patients has emerged as a promising new noninvasive biomarker for early detection of tumors and for predicting their molecular classifications. The rationale for this study was to identify subtype-specific molecular profiles of cell-free microRNAs for early detection of breast cancer in serum. Fifty-four early-stage breast cancers with 27 age-matched controls were selected for circulating microRNAs evaluation in the serum. The 54 cases were molecularly classified (luminal A, luminal B, luminal B Her2 positive, Her-2, triple negative). NanoString platform was used for digital detection and quantitation of 800 tagged microRNA probes and comparing the overall differences in serum microRNA expression from breast cancer cases with controls. We identified the 42 most significant (P ≤ 0.05, 1.5-fold) differentially expressed circulating microRNAs in each molecular subtype for further study. Of these microRNAs, 19 were significantly differentially expressed in patients presenting with luminal A, eight in the luminal B, ten in luminal B HER 2 positive, and four in the HER2 enriched subtype. AUC is high with suitable sensitivity and specificity. For the triple negative subtype miR-25-3p had the best accuracy. Predictive analysis of the mRNA targets suggests they encode proteins involved in molecular pathways such as cell adhesion, migration, and proliferation. This study identified subtype-specific molecular profiles of cell-free microRNAs suitable for early detection of breast cancer selected by comparison to the microRNA profile in serum for female controls without apparent risk of breast cancer. This molecular profile should be validated using larger cohort studies to confirm the potential of these miRNA for future use as early detection biomarkers that could avoid unnecessary biopsy in patients with a suspicion of breast cancer.
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McGuire, Andrew, Maire-Caitlin Casey, Ronan M. Waldron, Helen Heneghan, Olga Kalinina, Emma Holian, Ailbhe McDermott, et al. "Prospective Assessment of Systemic MicroRNAs as Markers of Response to Neoadjuvant Chemotherapy in Breast Cancer." Cancers 12, no. 7 (July 7, 2020): 1820. http://dx.doi.org/10.3390/cancers12071820.
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Neoadjuvant chemotherapy (NACT) is used in locally advanced breast cancer to reduce tumour burden prior to surgical resection. However, only a subset of NACT treated patients will respond to treatment or achieve a pathologic complete response (pCR). This multicenter, prospective study (CTRIAL-IE (ICORG) 10-11 study) evaluated circulating microRNA as novel non-invasive prognostic biomarkers of NACT response in breast cancer. Selected circulating microRNAs (Let-7a, miR-21, miR-145, miR-155, miR-195) were quantified from patients undergoing standard of care NACT treatment (n = 114) from whole blood at collected at diagnosis, and the association with NACT response and clinicopathological features evaluated. NACT responders had significantly lower levels of miR-21 (p = 0.036) and miR-195 (p = 0.017), compared to non-responders. Evaluating all breast cancer cases miR-21 was found to be an independent predictor of response (OR 0.538, 95% CI 0.308–0.943, p < 0.05). Luminal cancer NACT responders were found to have significantly decreased levels of miR-145 (p = 0.033) and miR-21 (p = 0.048), compared to non-responders. This study demonstrates the prognostic ability of miR-21, miR-195 and miR-145 as circulating biomarkers stratifying breast cancer patients by NACT response, identifying patients that will derive the maximum benefit from chemotherapy.
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Itani, Maha M., Farah J. Nassar, Arafat H. Tfayli, Rabih S. Talhouk, Ghada K. Chamandi, Abdul Rahman S. Itani, Joelle Makoukji, et al. "A Signature of Four Circulating microRNAs as Potential Biomarkers for Diagnosing Early-Stage Breast Cancer." International Journal of Molecular Sciences 22, no. 11 (June 6, 2021): 6121. http://dx.doi.org/10.3390/ijms22116121.
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Breast cancer (BC) is the most predominant type of cancer among women. The aim of this study is to find new biomarkers that can help in early detection of BC, especially for those who are too young to be screened using mammography as per guidelines. Using microRNA microarray, we previously showed dysregulation of 74 microRNAs in tumors from early BC patients as compared with normal adjacent tissues, which we were interested in studying in blood circulation. In this study, we investigated the expression of 12 microRNA (miR-21/miR-155/miR-23a/miR-130a/miR-145/miR-425-5p/miR-139-5p/miR-451/miR-195/miR-125b/miR-100, and miR-182) in the plasma of 41 newly diagnosed Lebanese BC patients with early invasive ductal carcinoma as compared with 32 healthy controls. Total RNA was extracted from plasma, and expression levels of miRNA of interest were measured using RT-qPCR followed by statistical analysis; miR-21, miR-155, miR-23a, miR-130a, miR-145, miR-425-5p, and miR-139-5p were significantly upregulated and miR-451 was significantly downregulated, in the plasma of BC patients as compared with healthy controls. The positively correlated miR-23a, miR-21, and miR-130a had a high diagnostic accuracy (86%). Importantly, the combination of miR-145/miR-425-5p/miR-139-5p/miR-130a scored the highest diagnostic accuracy of 95% with AUC = 0.97 (sensitivity 97% and specificity 91%). MicroRNAs are promising non-invasive diagnostic biomarkers for early-stage BC with the panel of miR-145/miR-425-5p/miR-139-5p/miR-130a having the highest diagnostic accuracy.
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Zhang, Xiaoqing, Qi He, Leiqin Sun, Yanfei Zhang, Shengying Qin, Junwei Fan, and Jianfeng Wang. "Comparing MicroRNA Profilings of Purified HER-2-Negative and HER-2-Positive Cells Validates miR-362-5p/Sema3A as Characteristic Molecular Change in Triple-Negative Breast Cancers." Disease Markers 2019 (December 18, 2019): 1–12. http://dx.doi.org/10.1155/2019/6057280.
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Background. HER-2 is a key molecule serving as the therapeutic target, prognostic biomarker, and classification marker in breast cancer. Accurate microRNA profilings had not been conducted in purified tumor cells of HER-2-negative and HER-2-positive tissue specimens obtained from breast cancer patients. Methods. (i) Differential expression microRNA discovery using laser capture microdissection- (LCM-) assisted specimen preparation and microRNA array chips on HER-2 overexpressing and triple-negative breast carcinoma (TNBC) subtype tissues, (ii) differential expression microRNA validation by quantitative real-time PCR, and (iii) independent validation on tissue microarray. Results. Five microRNAs (miR-20a-5p, miR-221-3p, miR-362-5p, miR-502-3p, and miR-222-3p) were screened and validated as upregulated microRNAs in TNBC cells comparing to HER-2 overexpressing cells using a microRNA array (5 cases in each group) and quantitative real-time PCR (20 cases in each group). The expression difference of miR-362-5p had the most significant statistical significance (p=0.0016) among the five microRNAs. The expression of miR-362-5p and its target gene Sema3A was further analyzed using in situ hybridization (ISH) and immunohistochemistry on standard tissue sections (n=150). 70.8% of HER-2-negative cells showed moderate expression of miR-362-5p whereas 20.4% HER-2-negative cells correlated with strong expression of miR-362-5p (p<0.0001). The proportion of patients with moderate/strong miR-362-5p expression in luminal, HER-2 overexpressing, and TNBC subtypes were 53.2%, 22.2%, and 74.3%, respectively (p=0.0002). High miR-362-5p expressers had shorter overall survival in the univariate analysis (p=0.046). There was a significant negative correlation between miR-362-5p and Sema3A expression (p<0.0001). The patients with negative/weak Sema3A protein expression had poorer prognosis than those with moderate (HR: 3.723, p=0.021) or strong (HR: 3.966, p=0.013) Sema3A protein expression in the multivariate analysis. Conclusions. miR-362-5p/Sema3A might provide a promising therapeutic pathway and represents a candidate therapeutic target of the TNBC subtype.
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Kim, Yong-Chul, and Mary L. Cutler. "MicroRNA-Dependent Targeting of RSU1 and the IPP Adhesion Complex Regulates the PTEN/PI3K/AKT Signaling Pathway in Breast Cancer Cell Lines." International Journal of Molecular Sciences 21, no. 15 (July 30, 2020): 5458. http://dx.doi.org/10.3390/ijms21155458.
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(1) Background: The microRNA (miR)-directed control of gene expression is correlated with numerous physiological processes as well as the pathological features of tumors. The focus of this study is on the role of miRs in the regulation of RSU1 and proteins in the IPP (integrin linked kinase, PINCH and parvin) complex. Because the IPP adaptor proteins link β integrins to actin cytoskeleton, and the RSU1 signaling protein connects the complex to the activation of cJun, ATF2 and the transcription of PTEN, their reduction by miRs has the potential to alter both adhesion and survival signaling. (2) Methods: Multiple database analyses were used to identify miRs that target RSU1 and PINCH1. miR transfection validated the effects of miRs on RSU1, PINCH1 and downstream targets in breast cancer cell lines. (3) Results: The miRs targeting RSU1 mRNA include miR-182-5p, -409-3p, -130a-3p, -221-3p, -744-5p and -106b-5p. Data show that miR-182-5p and -409-3p reduce RSU1, PINCH1 and inhibit the ATF2 activation of PTEN expression. miR-221-3p and miR-130a-3p target RSU1 and PINCH1 and, conversely, RSU1 depletion increases miR-221-3p and miR-130a-3p. (4) Conclusions: miRs targeting RSU1 and PINCH1 in mammary epithelial or luminal breast cancer cell lines reduced RSU1 signaling to p38 MAP kinase and ATF2, inhibiting the expression of PTEN. miR-221-3p, known to target PTEN and cell cycle regulators, also targets RSU1 and PINCH1 in luminal breast cancer cell lines.
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Kim, Jungho. "Identification of MicroRNAs as Diagnostic Biomarkers for Breast Cancer Based on the Cancer Genome Atlas." Diagnostics 11, no. 1 (January 11, 2021): 107. http://dx.doi.org/10.3390/diagnostics11010107.
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Breast cancer is the most common cancer among women worldwide. MicroRNAs (miRNAs or miRs) play an important role in tumorigenesis, and thus, they have been identified as potential targets for translational research with diagnostic, prognostic, and therapeutic markers. This study aimed to identify differentially expressed (DE) miRNAs in breast cancer using the Cancer Genome Atlas. The miRNA profiles of 755 breast cancer tissues and 86 adjacent non-cancerous breast tissues were analyzed using Multi Experiment Viewer; miRNA–mRNA network analyses and constructed KEGG pathways with the predicted target genes were performed. The clinical relevance of miRNAs was investigated using area under the receiver operating characteristic curve (AUC) analysis, sensitivity, and specificity. The analysis identified 28 DE miRNAs in breast cancer tissues, including nine upregulated and 19 downregulated miRNAs, compared to non-cancerous breast tissues (p < 0.001). The AUC for each DE miRNA, miR-10b, miR-21, miR-96, miR-99a, miR-100, miR-125b-1, miR-125b-2, miR-139, miR-141, miR-145, miR-182, miR-183, miR-195, miR-200a, miR-337, miR-429, and let-7c, exceeded 0.9, indicating excellent diagnostic performance in breast cancer. Moreover, 1381 potential target genes were predicted using the prediction database tool, miRNet. These genes are related to PD-L1 expression and PD-1 checkpoint in cancer, MAPK signaling, apoptosis, and TNF pathways; hence, they regulate the development, progression, and immune escape of cancer. Thus, these 28 miRNAs can serve as prospective biomarkers for the diagnosis of breast cancer. Taken together, these results provide insight into the pathogenic mechanisms and potential therapies for breast cancer.
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Kim, Jungho. "Identification of MicroRNAs as Diagnostic Biomarkers for Breast Cancer Based on the Cancer Genome Atlas." Diagnostics 11, no. 1 (January 11, 2021): 107. http://dx.doi.org/10.3390/diagnostics11010107.
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Breast cancer is the most common cancer among women worldwide. MicroRNAs (miRNAs or miRs) play an important role in tumorigenesis, and thus, they have been identified as potential targets for translational research with diagnostic, prognostic, and therapeutic markers. This study aimed to identify differentially expressed (DE) miRNAs in breast cancer using the Cancer Genome Atlas. The miRNA profiles of 755 breast cancer tissues and 86 adjacent non-cancerous breast tissues were analyzed using Multi Experiment Viewer; miRNA–mRNA network analyses and constructed KEGG pathways with the predicted target genes were performed. The clinical relevance of miRNAs was investigated using area under the receiver operating characteristic curve (AUC) analysis, sensitivity, and specificity. The analysis identified 28 DE miRNAs in breast cancer tissues, including nine upregulated and 19 downregulated miRNAs, compared to non-cancerous breast tissues (p < 0.001). The AUC for each DE miRNA, miR-10b, miR-21, miR-96, miR-99a, miR-100, miR-125b-1, miR-125b-2, miR-139, miR-141, miR-145, miR-182, miR-183, miR-195, miR-200a, miR-337, miR-429, and let-7c, exceeded 0.9, indicating excellent diagnostic performance in breast cancer. Moreover, 1381 potential target genes were predicted using the prediction database tool, miRNet. These genes are related to PD-L1 expression and PD-1 checkpoint in cancer, MAPK signaling, apoptosis, and TNF pathways; hence, they regulate the development, progression, and immune escape of cancer. Thus, these 28 miRNAs can serve as prospective biomarkers for the diagnosis of breast cancer. Taken together, these results provide insight into the pathogenic mechanisms and potential therapies for breast cancer.
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Laqtom, Nouf N., Khloud M. Algothmi, and Amani H. Bakhribah. "Inferring Transcription Factors and microRNAs Associated with Elevated Expression of the Oncogenic B-Cell Lymphoma 11A in Triple Negative Breast Cancer." Journal of King Abdulaziz University - Medical Sciences 23, no. 3 (September 30, 2016): 9–21. http://dx.doi.org/10.4197/med.23-3.2.
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B-cell lymphoma 11A, a transcriptional repressor, is highly expressed in triple negative breast cancer. The in vitro studies and animal models provide initial evidence suggesting that the knockdown of B-cell lymphoma 11A has a therapeutic eff ect on breast cancer. Defining the regulators driving the high expression of B-cell lymphoma 11A is important to understand its cancer-related functions. Among these regulators, transcription factors and microRNAs are critical for gene expression and associated with expression perturbations. Firstly, weidentifi ed the transcription factors that potentially interact with B-cell lymphoma 11A promoter. Based on bioinformatics prediction and multiple Omics datasets, two upregulated transcriptional activators Zinc Finger BED-Type Containing 4 and E2F Transcription Factor 1 in triple negative breast cancer were found to have seven sites within B-cell lymphoma 11A promoter. Secondly, we aimed to determine a putative set of microRNA that can mediate the post-transcriptional repression of B-cell lymphoma 11A. miR-513a-5p, miR-139-5p, miR-1179, miR-140-5p, and miR-542-3p, harboring at least one site of interaction with B-cell lymphoma 11A 3 untranslated region, were found inhibited in triple negative breast cancer. Taken together, the combinatorial regulation by transcription factors and microRNAs provide valuable information for further investigation on controlling the expression level of B-cell lymphoma 11A in triple negative breast cancer.
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Cai, Fenglin, Luhong Chen, Yuting Sun, Chunlan He, Deyuan Fu, and Jinhai Tang. "MiR-539 inhibits the malignant behavior of breast cancer cells by targeting SP1." Biochemistry and Cell Biology 98, no. 3 (June 2020): 426–33. http://dx.doi.org/10.1139/bcb-2019-0111.
Full textAbstract:
The aberrant expression of microRNAs (miRNAs) is involved in the initiation and progression of human cancers. In our study, we found that miR-539 was down-regulated in breast cancer tissues and cell lines. Decreased expression of miR-539 was significantly associated with lymph node metastasis in patients with breast cancer. Overexpression of miR-539 inhibited the proliferation and promoted apoptosis of breast cancer cells. Moreover, highly expressed miR-539 significantly suppressed the epithelial–mesenchymal transition (EMT) and sensitized cells to cisplatin treatment. Mechanistically, miR-539 was found to target the specificity protein 1 (SP1) and down-regulated the expression of SP1 in breast cancer cells. Knockdown of miR-539 consistently increased the expression of SP1. The expression of miR-539 in breast cancer tissues was negatively correlated with the expression of SP1. Restoration of SP1 significantly attenuated the inhibitory effect of miR-539 on the proliferation of breast cancer cells. Taken together, our results indicate that miR-539 has a tumor suppressive role in breast cancer via targeting SP1, suggesting miR-539 as a promising target for the diagnosis of breast cancer.
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Peng, Ziqi, Boyang Xu, and Feng Jin. "Circular RNA hsa_circ_0000376 Participates in Tumorigenesis of Breast Cancer by Targeting miR-1285-3p." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382092847. http://dx.doi.org/10.1177/1533033820928471.
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This study was designed to identify novel circular RNAs and the related regulatory axis to provide research targets for the diagnosis and treatment of breast cancer. The circular RNA expression microarray “GSE101123” related to breast cancer was downloaded from the Gene Expression Omnibus database. The differentially expressed circular RNAs between tumor and normal samples were screened using Limma package. The targeted microRNAs of the differentially expressed circular RNAs and the targeted messenger RNAs of the microRNAs were predicted using miRanda and miRWalk, respectively, and a circular RNAs–microRNAs–messenger RNAs network was constructed. Then, functional enrichment analysis, protein–protein interaction network construction, and drug–gene interaction analysis were conducted for the messenger RNAs. A total of 11 differentially expressed circular RNAs were identified between the breast cancer and normal samples, of which 3 were upregulated, while 8 were downregulated. The circular RNA–microRNA–messenger RNA network contained 1 circular RNA (hsa_circ_0000376), 2 microRNAs (miR-1285-3p and miR-1286), and 353 messenger RNAs. The protein–protein interaction network contained 150 nodes and 240 interactions. The hub genes in the protein–protein interaction network were all targeted messenger RNAs of miR-1285-3p that were significantly enriched in the ubiquitin–proteasome system, apoptosis, cell cycle arrest–related pathways, and cancer-related pathways involving SMAD specific E3 ubiquitin protein ligase 1, β-transducin repeat containing E3 ubiquitin protein ligase, tumor protein P53 among others. Twenty-two drugs were predicted to target 4 messenger RNAs, including tumor protein P53. A novel circular RNA, hsa_circ_0000376, was identified in breast cancer that may act as a sponge targeting miR-1285-3p expression which through its target genes, SMURF1, BTRC, and TP53, may further regulate tumorigenesis.
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Tanman, Ümmügülsüm, Sevcan Yangın, and Demet Cansaran-Duman. "Determination of Dysregulated miRNA Expression Levels by qRT-PCR after the Application of Usnic Acid to Breast Cancer." Anti-Cancer Agents in Medicinal Chemistry 20, no. 5 (May 28, 2020): 548–58. http://dx.doi.org/10.2174/1871520619666190923163552.
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Background and Purpose: Breast cancer still remains to be one of the most threatening cancer types in women. Recent studies have allowed scientists to better investigate the potential use of natural compounds in the treatment of breast cancers. Usnic acid is a secondary metabolite extracted from lichen species and has many biological activities. The response of microRNAs regulated by drug molecules may provide useful diagnostic and prognostic biomarkers, as well as potential therapeutics for breast cancers. Although the aberrant expression of microRNAs was observed after drug treatment, the regulatory mechanisms remain partially known. Micro RNAs (miRNAs) play an important role in gene regulation at the post-transcriptional level. Methods: In this study, we used quantitative Real-Time PCR (qRT-PCR) technology to demonstrate that usnic acid significantly changes the expression profile of miRNAs. Results: Eleven miRNAs were significantly and differentially expressed in breast cancer cells after treatment with usnic acid. Three miRNAs were up-regulated, while eight were down-regulated in usnic acid treated cells. Target prediction and GO analysis revealed many target genes and their related pathways that are potentially regulated by usnic acid regulated differentially expressed miRNAs. We found that usnic acid treatment caused significant changes in the expression of hsa-miR-5006-5p, hsa-miR-892c-3p, hsa-miR-4430, hsa-miR-5194, hsa-miR-3198, hsa-miR-3171, hsa-miR-933 and hsa-miR-185-3p in breast cancer cells. Conclusions: Usnic acid response miRNAs might play important regulatory roles in the tumorigenesis and development of breast cancer, and they could serve as prognostic predictors for breast cancer patients.
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Corcoran, Claire, Anne M. Friel, Michael J. Duffy, John Crown, and Lorraine O'Driscoll. "Intracellular and Extracellular MicroRNAs in Breast Cancer." Clinical Chemistry 57, no. 1 (January 1, 2011): 18–32. http://dx.doi.org/10.1373/clinchem.2010.150730.
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BACKGROUND Successful treatment of breast cancer is enhanced by early detection and, if possible, subsequent patient-tailored therapy. Toward this goal, it is essential to identify and understand the most relevant panels of biomarkers, some of which may also have relevance as therapeutic targets. METHODS We critically reviewed published literature on microRNAs (miRNAs) as relevant to breast cancer. SUMMARY Since the initial recognition of the association of miRNAs with breast cancer in 2005, studies involving cell lines, in vivo models, and clinical specimens have implicated several functions for miRNAs, including suppressing oncogenesis and tumors, promoting or inhibiting metastasis, and increasing sensitivity or resistance to chemotherapy and targeted agents in breast cancer. For example, miR-21 is overexpressed in both male and female breast tumors compared with normal breast tissue and has been associated with advanced stage, lymph node positivity, and reduced survival time. miR-21 knock-down in cell-line models has been associated with increased sensitivity to topotecan and taxol in vitro and the limitation of lung metastasis in vivo. Furthermore, the discovery of extracellular miRNAs (including miR-21), existing either freely or in exosomes in the systemic circulation, has led to the possibility that such molecules may serve as biomarkers for ongoing patient monitoring. Although additional investigations are necessary to fully exploit the use of miRNAs in breast cancer, there is increasing evidence that miRNAs have potential not only to facilitate the determination of diagnosis and prognosis and the prediction of response to treatment, but also to act as therapeutic targets and replacement therapies.
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Lu, Huajun, Chaoqun Wang, Lijun Xue, Qi Zhang, Frank Luh, Jianghai Wang, Tiffany G. Lin, Yun Yen, and Xiyong Liu. "Human Mitotic Centromere-Associated Kinesin Is Targeted by MicroRNA 485-5p/181c and Prognosticates Poor Survivability of Breast Cancer." Journal of Oncology 2019 (April 3, 2019): 1–13. http://dx.doi.org/10.1155/2019/2316237.
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Purpose. This study aims to evaluate the prognostic value of human Mitotic Centromere-Associated Kinesin (MCAK), a microtubule-dependent molecular motor, in breast cancers. The posttranscriptional regulation of MCAK by microRNAs will also be explored.Methods. The large-scale gene expression datasets of breast cancer (total n=4,677) were obtained from GEO, NKI, and TCGA database. Kaplan-Meier and Cox analyses were used for survival analysis. MicroRNAs targeting MCAK were predicted by bioinformatic analysis and validated by a dual-luciferase reporter assay.Results. The expression of MCAK was significantly associated with aggressive features of breast cancer, including tumor stage, Elston grade, and molecular subtypes, for global gene expression datasets of breast cancer (p<0.05). Overexpression of MCAK was significantly associated with poor outcome in a dose-dependent manner for either ER-positive or ER-negative breast cancer. Evidence from bioinformatic prediction, coexpression assays, and gene set enrichment analyses suggested that miR-485-5p and miR-181c might target MCAK and suppress its expression. A 3’UTR dual-luciferase target reporter assay demonstrated that miR-485-5p and miR-181c mimics specifically inhibited relative Firefly/Renilla luciferase activity by about 50% in corresponding reporter plasmids. Further survival analysis also revealed that miR-485-5p (HR=0.59, 95% CI 0.37-0.92) and miR-181c (HR=0.54, 95% CI 0.34-0.84) played opposite roles of MCAK (HR=2.80, 95% CI 1.77-4.57) and were significantly associated with better outcome in breast cancers.Conclusion. MCAK could serve as a prognostic biomarker for breast cancers. miR-485-5p and miR-181c could specifically target and suppress the MCAK gene expression in breast cancer cells.
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Jena, Manoj Kumar. "MicroRNAs in the development and neoplasia of the mammary gland." F1000Research 6 (October 3, 2017): 1018. http://dx.doi.org/10.12688/f1000research.12005.2.
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Study on the role of microRNAs (miRs) as regulators of gene expression through posttranscriptional gene silencing is currently gaining much interest,due to their wide involvement in different physiological processes. Understanding mammary gland development, lactation, and neoplasia in relation to miRs is essential. miR expression profiling of the mammary gland from different species in various developmental stages shows their role as critical regulators of development. miRs such as miR-126, miR-150, and miR-145 have been shown to be involved in lipid metabolism during lactation. In addition, lactogenic hormones influence miR expression as evidenced by overexpression of miR-148a in cow mammary epithelial cells, leading to enhanced lactation. Similarly, the miR-29 family modulates lactation-related gene expression by regulating DNA methylation of their promoters. Besides their role in development, lactation and involution, miRs are responsible for breast cancer development. Perturbed estrogen (E2) signaling is one of the major causes of breast cancer. Increased E2 levels cause altered expression of ERα, and ERα-miR cross-talk promotes tumour progression. miRs, such as miR-206, miR-34a, miR-17-5p, and miR-125 a/b are found to be tumour suppressors; whereas miR-21, miR-10B, and miR-155 are oncogenes. Oncogenic miRs like miR-21, miR-221, and miR-210 are overexpressed in triple negative breast cancer cases which can be diagnostic biomarker for this subtype of cancer. This review focuses on the recent findings concerning the role of miRs in developmental stages of the mammary gland (mainly lactation and involution stages) and their involvement in breast cancer progression. Further studies in this area will help us to understand the molecular details of mammary gland biology, as well as miRs that could be therapeutic targets of breast cancer.
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Xiao, Humphries, Yang, and Wang. "MiR-205 Dysregulations in Breast Cancer: The Complexity and Opportunities." Non-Coding RNA 5, no. 4 (November 19, 2019): 53. http://dx.doi.org/10.3390/ncrna5040053.
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MicroRNAs (miRNAs) are endogenous non-coding small RNAs that downregulate target gene expression by imperfect base-pairing with the 3′ untranslated regions (3′UTRs) of target gene mRNAs. MiRNAs play important roles in regulating cancer cell proliferation, stemness maintenance, tumorigenesis, cancer metastasis, and cancer therapeutic resistance. While studies have shown that dysregulation of miRNA-205-5p (miR-205) expression is controversial in different types of human cancers, it is generally observed that miR-205-5p expression level is downregulated in breast cancer and that miR-205-5p exhibits a tumor suppressive function in breast cancer. This review focuses on the role of miR-205-5p dysregulation in different subtypes of breast cancer, with discussions on the effects of miR-205-5p on breast cancer cell proliferation, epithelial–mesenchymal transition (EMT), metastasis, stemness and therapy-resistance, as well as genetic and epigenetic mechanisms that regulate miR-205-5p expression in breast cancer. In addition, the potential diagnostic and therapeutic value of miR-205-5p in breast cancer is also discussed. A comprehensive list of validated miR-205-5p direct targets is presented. It is concluded that miR-205-5p is an important tumor suppressive miRNA capable of inhibiting the growth and metastasis of human breast cancer, especially triple negative breast cancer. MiR-205-5p might be both a potential diagnostic biomarker and a therapeutic target for metastatic breast cancer.
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Sochor, Marek, Petra Basova, Michal Pesta, Jiri Bartos, and Tomas Stopka. "Oncogenic microRNAs to predict relapse in early breast cancer patients." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23021-e23021. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23021.
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e23021 Background: Early breast cancer is a frequent female disease with different outcomes. New approaches are needed in order to improve its prognosis. MicroRNAs (miRs) are modulators of gene expression and act as oncogenes and function to inhibit tumor suppressors and to promote metastasizing. Monitoring of miRs could be of benefit to the prognosis of EBC patients. Methods: We prospectively collected sera from 133 EBC patients (follow-up 53,25 months) in 3 time points (before I and after surgery II, after therapy III). Patients were stratified into high and low-risk groups according to HR, HER2, Ki-67, grade, LN. For RNA isolation serum was used followed by RT-qPCR and was applied longitudinal multivariate data analysis. Aim of the project was to determine serum expression of miR-155, miR-19a, miR-181b, miR-24 in 3 time points, to find difference in expressions between high and low-risk groups, to find association between miRs and clinical/pathological risk factors and associations in miRs expression and prognosis of EBC. Results: EBC patients significantly over-express miRs in time point I. In time point II the levels of miR-155, miR-181b, miR-24 significantly decreased ( p< 0.05). miR-19a decreased in time point III ( p= 0.00869). Levels of miR-155, miR-19a, miR-181b, miR-24 are significantly more abundant in high-risk in comparison to low-risk patients ( p< 0.05) and decrease upon therapy. The multivariate GEE model revealed that miR-155, miR-24 were predictive of the relapse ( p= 0.025 and 0.041). miR-19a, miR-181b are insignificant with respect to the relapse ( p> 0.05). Triple-negativity, HER2+, grade III, LN+ have no effect on the probability of relapse ( p> 0.05) when miRs are simultaneously taken into an account. The only risk factor that makes the prediction of relapse more precise is Ki-67 > 20% ( p= 0.013 in case of miR-155 and p= 0.023 in case of miR-24). Conclusions: OncomiRs are significantly more abundant in EBC patients at diagnosis and decline after therapy. Differences in miR levels reflect EBC risk groups. The data shows that miR-155 and miR-24 enable monitoring of EBC and predict relapse independently of clinical/pathological risk factors. Combining the miR levels with Ki-67 expression further specifies the relapse probability.
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Lee, Soo Jung, Jae-Hwan Jeong, Seung Hee Kang, Jieun Kang, Eun Ae Kim, Jeeyeon Lee, Jin Hyang Jung, Ho Yong Park, and Yee Soo Chae. "MicroRNA-137 Inhibits Cancer Progression by Targeting Del-1 in Triple-Negative Breast Cancer Cells." International Journal of Molecular Sciences 20, no. 24 (December 6, 2019): 6162. http://dx.doi.org/10.3390/ijms20246162.
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MicroRNAs (miRNAs) can be used to target a variety of human malignancy by targeting their oncogenes or tumor suppressor genes. The developmental endothelial locus-1 (Del-1) might be under miRNA regulation. This study investigated microRNA-137 (miR-137) function and Del-1 expression in triple-negative breast cancer (TNBC) cells and tissues. Del-1 mRNA and miRNA-137 levels were determined via qRT-PCR in breast cancer cells (MDA-MB-231, MCF7, SK-BR3, and T-47D) and tissues from 30 patients with TNBC. The effects of miR-137 on cell proliferation, migration, and invasion were determined using MTT assays, wound healing, and Matrigel transwell assays. The luciferase reporter assay revealed direct binding of miR-137 to the 3′-UTR of Del-1. miR-137 inhibited cell proliferation, migration, and invasion of MDA-MB-231 cells. Among the 30 TNBC specimens, miR-137 was downregulated and Del-1 level in plasma was significantly elevated relative to normal controls. It is concluded that miR-137 regulates Del-1 expression in TNBC by directly binding to the Del-1 gene and cancer progression. The results implicate miR-137 as a new therapeutic biomarker for patients with TNBC.
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de Anda-Jáuregui, Guillermo, Jesús Espinal-Enríquez, Diana Drago-García, and Enrique Hernández-Lemus. "Nonredundant, Highly Connected MicroRNAs Control Functionality in Breast Cancer Networks." International Journal of Genomics 2018 (May 29, 2018): 1–10. http://dx.doi.org/10.1155/2018/9585383.
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Alterations to transcriptional regulation are an important factor in breast cancer. Noncoding RNA, such as microRNA (miR), have very influential roles in the transcriptional regulation of genes. Transcriptional regulation can be successfully modeled and analyzed using complex network theory. Particularly, interactions between two distinct classes of biological elements, such as miR and genes, can be approached through the bipartite network formalism. Based on bipartite network properties, it is possible to identify highly influential miRs in the network, such as those that have a large number of connections indicating regulation of a large set of genes. Some miRs in a network are nonredundant, which indicates that they are solely responsible of the regulation of a particular set of genes, which in turn may be associated to a particular biological process. We hypothesize that highly influential, nonredundant miRs, which we call Commodore miRs (Cdre-miRs), have an important role on the control of biological functions through transcriptional networks. In this work, we analyze the regulation of gene expression by miRs in healthy and cancerous breast tissue using bipartite miR-gene networks inferred from the Cancer Genome Atlas (TCGA) expression data. We observe differences in the degree, clustering coefficient and redundancy distributions for miRs and genes in the network, indicating differences in the way that these elements interact with each other. Furthermore, we identify a small set of five Cdre-miRs in the breast cancer network: miR-190b, miR-let7i, miR-292-b, miR-511, and miR-141. The neighborhood of genes controlled by each of these miRs is involved in particular biological functions such as dynein structure-associated processes, immune response, angiogenesis, cytokine activity, and cell motility. We propose that these Cdre-miRs are important control elements of biological functions deregulated in breast cancer.
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Alam, Farheen, Fatima Mezhal, Hussain EL Hasasna, Vidhya A. Nair, SR Aravind, Maha Saber Ayad, Ahmed El-Serafi, and Wael M. Abdel-Rahman. "The role of p53-microRNA 200-Moesin axis in invasion and drug resistance of breast cancer cells." Tumor Biology 39, no. 9 (September 2017): 101042831771463. http://dx.doi.org/10.1177/1010428317714634.
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This study aimed to analyze the expression of microRNAs in relation to p53 status in breast cancer cells and to delineate the role of Moesin in this axis. We used three isogenic breast carcinoma cell lines MCF7 (with wild-type p53), 1001 (MCF7 with mutated p53), and MCF7-E6 (MCF7 in which p53 function was disrupted). MicroRNA expression was analyzed using microarray analysis and confirmed by real-time polymerase chain reaction. The 1001 clone with mutant p53 showed 22 upregulated and 25 downregulated microRNAs. The predicted targets of these 47 microRNAs were >700 human genes belonging to interesting functional groups such as stem cell development and maintenance. The most significantly downregulated microRNAs in the p53-mutant cell line were from the miR-200 family. We focused on miR-200c which targets many transcripts involved in epithelial-to-mesenchymal transition including Moesin. We found that Moesin was expressed in 1001 but not in its p53 wild-type parental MCF7 consistent with the observed mesenchymal features in the 1001, such as vimentin positivity, E-cadherin negativity, and ZEB1 positivity in addition to the morphological changes. After Moesin silencing, the p53-mutant cells 1001 reverted from mesenchymal-to-epithelial phenotype and showed subtle reduction in migration and invasion and loss of ZEB1 and SNAIL expression. Interestingly, Moesin silencing restored the 1001 sensitivity to Doxorubicin. These results indicate that loss of miR-200c, as a consequence of p53 mutation, can upregulate Moesin oncogene and thus promote carcinogenesis. Moesin may play a role in metastasis and drug resistance of breast cancer.
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Balachandran, Akilandeswari A., Leon M. Larcher, Suxiang Chen, and Rakesh N. Veedu. "Therapeutically Significant MicroRNAs in Primary and Metastatic Brain Malignancies." Cancers 12, no. 9 (September 7, 2020): 2534. http://dx.doi.org/10.3390/cancers12092534.
Full textAbstract:
Brain cancer is one among the rare cancers with high mortality rate that affects both children and adults. The most aggressive form of primary brain tumor is glioblastoma. Secondary brain tumors most commonly metastasize from primary cancers of lung, breast, or melanoma. The five-year survival of primary and secondary brain tumors is 34% and 2.4%, respectively. Owing to poor prognosis, tumor heterogeneity, increased tumor relapse, and resistance to therapies, brain cancers have high mortality and poor survival rates compared to other cancers. Early diagnosis, effective targeted treatments, and improved prognosis have the potential to increase the survival rate of patients with primary and secondary brain malignancies. MicroRNAs (miRNAs) are short noncoding RNAs of approximately 18–22 nucleotides that play a significant role in the regulation of multiple genes. With growing interest in the development of miRNA-based therapeutics, it is crucial to understand the differential role of these miRNAs in the given cancer scenario. This review focuses on the differential expression of ten miRNAs (miR-145, miR-31, miR-451, miR-19a, miR-143, miR-125b, miR-328, miR-210, miR-146a, and miR-126) in glioblastoma and brain metastasis. These miRNAs are highly dysregulated in both primary and metastatic brain tumors, which necessitates a better understanding of their role in these cancers. In the context of the tumor microenvironment and the expression of different genes, these miRNAs possess both oncogenic and/or tumor-suppressive roles within the same cancer.
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Jena, Manoj Kumar. "MicroRNAs in the development and neoplasia of the mammary gland." F1000Research 6 (June 28, 2017): 1018. http://dx.doi.org/10.12688/f1000research.12005.1.
Full textAbstract:
Study on the role of microRNAs (miRs) as regulators of gene expression through posttranscriptional gene silencing is currently gaining much interest,due to their wide involvement in different physiological processes. Understanding mammary gland development, lactation, and neoplasia in relation to miRs is essential. miR expression profiling of the mammary gland from different species in various developmental stages shows their role as critical regulators of development. miRs such as miR-126, miR-150, and miR-145 have been shown to be involved in lipid metabolism during lactation. In addition, lactogenic hormones influence miR expression as evidenced by overexpression of miR-148a in cow mammary epithelial cells, leading to enhanced lactation. Similarly, the miR-29 family modulates lactation-related gene expression by regulating DNA methylation of their promoters. Besides their role in development, lactation and involution, miRs are responsible for breast cancer development. Perturbed estrogen (E2) signaling is one of the major causes of breast cancer. Increased E2 levels cause altered expression of ERα, and ERα-miR cross-talk promotes tumour progression. miRs, such as miR-206, miR-34a, miR-17-5p, and miR-125 a/b are found to be tumour suppressors; whereas miR-21, miR-10B, and miR-155 are oncogenes.Studies using an ACI rat model showed similar findings of miR dysregulation due to excess E2, and a natural phenol antioxidant ellagic acid showed therapeutic properties by reversing the miR dysregulation. This review focuses on the recent findings concerning the role of miRs in developmental stages of the mammary gland (mainly lactation and involution stages) and their involvement in breast cancer progression. Further studies in this area will help us understand the molecular details of mammary gland biology,as well as miRs that could be therapeutic targets of breast cancer.
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Shai, Ayelet, Avital Gilam, Mariana Steiner, and Noam Shomron. "Involvement of microRNA in the regulation of progesterone receptor in breast cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 578. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.578.
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578 Background: The progesterone receptor (PgR) is a prognostic factor in ER positive breast cancers treated by adjuvant hormonal treatment. While PgR protein is usually assessed by immunohistochemistry (IHC), RT-PCR measurement of mRNA levels is provided by Oncotype Dx and other tests. Between 20-40% of tumors are discrepant in IHC and RT-PCR PgR expression, reflecting either technical problems or biological mechanisms. MicroRNAs regulate gene expression either at the mRNA or the protein translation level. Our hypothesis is that the latter potentially explains discrepancies between IHC and RT-PCR results. Methods: ER positive tumors were divided to three groups by PgR expression according to IHC and RT-PCR: (i) positive by IHC; (ii) negative by IHC and high mRNA levels by RT-PCR; (iii) negative by IHC and low mRNA levels by RT-PCR. RNA was extracted from tumors and adjacent normal tissue and the expression of PgR and microRNAs was assessed by RT-PCR. In addition, microRNAs were transfected into MCF-7 cells. The levels of PgR mRNA and protein were analyzed. Results: The PgR gene contains potential conserved binding sites for MicroRNAs 23a, 181a, 135a and 26b. Of these, miR- 23a and miR-181a showed inverse expression relative to the PgR expression in normal and tumor tissue, as expected. MicroRNA levels were determined in tumors of all three groups. The highest expression of microRNAs 23a, 181a and 26b was seen in IHC negative tumors with low levels of mRNA. Intermediate expression was seen in IHC negative tumors with high mRNA levels, and the lowest expression was detected in IHC positive tumors. Preliminary results suggest that over expression of microRNAs 23a, 181a and 26b in MCF7 cells decreased PgR levels. Conclusions: Our results suggest that microRNAs 23a , 181a and 26b regulate the level of the progesterone receptor in breast cancer and that tumors with relatively high mRNA levels may be deficient in PgR protein due to downregulation by microRNAs. [Table: see text]
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Malhotra, Poonam, Graham Read, and Joanne Weidhaas. "Breast Cancer and miR-SNPs: The Importance of miR Germ-Line Genetics." Non-Coding RNA 5, no. 1 (March 20, 2019): 27. http://dx.doi.org/10.3390/ncrna5010027.
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Recent studies in cancer diagnostics have identified microRNAs (miRNAs) as promising cancer biomarkers. Single nucleotide polymorphisms (SNPs) in miRNA binding sites, seed regions, and coding sequences can help predict breast cancer risk, aggressiveness, response to stimuli, and prognosis. This review also documents significant known miR-SNPs in miRNA biogenesis genes and their effects on gene regulation in breast cancer, taking into account the genetic background and ethnicity of the sampled populations. When applicable, miR-SNPs are evaluated in the context of other patient factors, including mutations, hormonal status, and demographics. Given the power of miR-SNPs to predict patient cancer risk, prognosis, and outcomes, further study of miR-SNPs is warranted to improve efforts towards personalized medicine.
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Zhao, Mingchuan, Mengmeng Zhang, Zhonghua Tao, Jun Cao, Leiping Wang, and Xichun Hu. "miR-331-3p Suppresses Cell Proliferation in TNBC Cells by Downregulating NRP2." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382090582. http://dx.doi.org/10.1177/1533033820905824.
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Purpose: Triple-negative breast cancer is characterized by fast progression with high possible for metastasis and poor survival. Dysfunction of microRNAs plays an important role in the initiation and progression of cancer. Our previous microRNA-seq data indicated the downregulation of miR-331-3p in triple-negative breast cancer tissues compared with that of the noncancer tissues. However, the function of miR-331-3p in triple-negative breast cancer remains largely unknown. Herein, the involvement of miR-331-3p in triple-negative breast cancer was investigated and the therapeutic potential of miR-331-3p was also explored. Methods: Real-time quantitative polymerase chain reaction was performed to detect the expression of miR-331-3p in triple-negative breast cancer tissues and cell lines. The cell proliferation was determined by the cell counting kit-8 assay. Apoptosis of triple-negative breast cancer cells was examined by annexin V/propidium iodide staining. miRDB database was used to predict the potential targets of miR-331-3p. Western blot was performed to examine the expression of the target protein. Results: miR-331-3p was significantly downregulated in triple-negative breast cancer tissues and cell line. Lower miR-331-3p expression was significantly correlated with the tumor size, TNM stage, and lymph node metastasis of patients with triple-negative breast cancer. Functional experiments showed that the overexpression of miR-331-3p inhibited the proliferation and increased apoptosis of triple-negative breast cancer cells. Neuropilin-2 was identified as a target of miR-331-3p, which harbored binding site of miR-331-3p in its 3′-untranslated region. Overexpression of miR-331-3p decreased the messenger RNA and protein levels of neuropilin-2 in triple-negative breast cancer cells. Restoration of neuropilin-2 partially reversed the inhibitory effects of miR-331-3p on the proliferation of triple-negative breast cancer cells. Conclusions: Our results demonstrated the novel function of miR-331-3p/neuropilin-2 signaling in regulating the malignant behaviors of triple-negative breast cancer cells, which suggested miR-331-3p as a potential target for the treatment of triple-negative breast cancer.
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Dombkowski, Alan A., Zakia Sultana, Douglas B. Craig, and Hasan Jamil. "In silico Analysis of Combinatorial microRNA Activity Reveals Target Genes and Pathways Associated with Breast Cancer Metastasis." Cancer Informatics 10 (January 2011): CIN.S6631. http://dx.doi.org/10.4137/cin.s6631.
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Aberrant microRNA activity has been reported in many diseases, and studies often find numerous microRNAs concurrently dysregulated. Most target genes have binding sites for multiple microRNAs, and mounting evidence indicates that it is important to consider their combinatorial effect on target gene repression. A recent study associated the coincident loss of expression of six microRNAs with metastatic potential in breast cancer. Here, we used a new computational method, miR-AT!, to investigate combinatorial activity among this group of microRNAs. We found that the set of transcripts having multiple target sites for these microRNAs was significantly enriched with genes involved in cellular processes commonly perturbed in metastatic tumors: cell cycle regulation, cytoskeleton organization, and cell adhesion. Network analysis revealed numerous target genes upstream of cyclin D1 and c-Myc, indicating that the collective loss of the six microRNAs may have a focal effect on these two key regulatory nodes. A number of genes previously implicated in cancer metastasis are among the predicted combinatorial targets, including TGFB1, ARPC3, and RANKL. In summary, our analysis reveals extensive combinatorial interactions that have notable implications for their potential role in breast cancer metastasis and in therapeutic development.
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Ma, Peng, Kan Ni, Jing Ke, Wenyi Zhang, Ying Feng, and Qinsheng Mao. "miR-448 inhibits the epithelial-mesenchymal transition in breast cancer cells by directly targeting the E-cadherin repressor ZEB1/2." Experimental Biology and Medicine 243, no. 5 (January 25, 2018): 473–80. http://dx.doi.org/10.1177/1535370218754848.
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Recently, accumulating evidence provides that dysregulation of microRNAs (miRNAs) is considered to play vital roles in tumor progression. Based on microRNA arrays, we found that microRNA-448 (miR-448) was significantly downregulated in breast cancer tissue specimens. In our study, we were in an effort to clarify the function, the direct target gene, and the molecular mechanisms of miR-448 in breast cancer. By quantitative RT–PCR, we analyzed the expression of miR-448 in 16 patients with BC. Overexpression of miR-448 was established by transfecting miR-448-mimics into MDA-MB-231 and MCF-7 cells, methyl thiazolyl- tetrazolium and colony formation assays were performed to evaluate its effects on cell proliferation. We also performed cell migration and invasion assays in breast cells overexpressing miRNA-448. All the results indicated that overexpression of miR-448 in breast cancer cells markedly suppressed cell proliferation, migration, and invasion. Through the quantitative RT–PCR and Western Blots, we also evaluated epithelial–mesenchymal transition. We found that overexpression of miR-448 also downregulated the expression of vimentin, a well-known mesenchymal marker. Meanwhile, the epithelial marker E-cadherin was unregulated, suggesting that miR-448 inhibited epithelial–mesenchymal transition . Bioinformatics assay coupled with Western Blot and luciferase assays revealed that miR-448 directly binds to the 3′UTR of E-cadherin repressor ZEB1/2, resulting in suppression of epithelial–mesenchymal transition in breast cancer cells. Impact statement In our study, we revealed that miR-448 played a vital role in breast cancer development and we also uncovered the mechanisms of it. Following is the short description of the main findings: miR-448 is downregulated in BC. miR-448 regulates cell proliferation, migration, and invasion in BC. miR-448 specifically regulates ZEB1/2 through binding to the 3′UTR in BC cells. miR-448 inhibits cell migration, invasion, and EMT by targeting to the 3′UTR of ZEB1/2.
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Song, Shuxuan, Kelsey S. Johnson, Henry Lujan, Sahar H. Pradhan, Christie M. Sayes, and Joseph H. Taube. "Nanoliposomal Delivery of MicroRNA-203 Suppresses Migration of Triple-Negative Breast Cancer through Distinct Target Suppression." Non-Coding RNA 7, no. 3 (July 27, 2021): 45. http://dx.doi.org/10.3390/ncrna7030045.
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Triple-negative breast cancers affect thousands of women in the United States and disproportionately drive mortality from breast cancer. MicroRNAs are small, non-coding RNAs that negatively regulate gene expression post-transcriptionally by inhibiting target mRNA translation or by promoting mRNA degradation. We have identified that miRNA-203, silenced by epithelial–mesenchymal transition (EMT), is a tumor suppressor and can promote differentiation of breast cancer stem cells. In this study, we tested the ability of liposomal delivery of miR-203 to reverse aspects of breast cancer pathogenesis using breast cancer and EMT cell lines. We show that translationally relevant methods for increasing miR-203 abundance within a target tissue affects cellular properties associated with cancer progression. While stable miR-203 expression suppresses LASP1 and survivin, nanoliposomal delivery suppresses BMI1, indicating that suppression of distinct mRNA target profiles can lead to loss of cancer cell migration.
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Kalinina, Tatiana, Vladislav Kononchuk, Efim Alekseenok, Darya Obukhova, Sergey Sidorov, Dmitry Strunkin, and Lyudmila Gulyaeva. "Expression of Estrogen Receptor- and Progesterone Receptor-Regulating MicroRNAs in Breast Cancer." Genes 12, no. 4 (April 16, 2021): 582. http://dx.doi.org/10.3390/genes12040582.
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In ~70% of breast cancer (BC) cases, estrogen and progesterone receptors (ER and PR) are overexpressed, which can change during tumor progression. Expression changes of these receptors during cancer initiation and progression can be caused by alterations in microRNA (miR, miRNA) expression. To assess the association of BC progression with aberrant expression of miRNAs that target ER and PR mRNAs, we quantified miR-19b, -222, -22, -378a, and -181a in BC samples (n = 174) by real-time PCR. Underexpression of miR-222 and miR-378a in stage T2–T4 BC was characteristic for HER2-overexpressing tumors. In addition, the expression of miR-181a and miR-378a was higher in these tumors than in tumors with a HER2 IHC score of 0 or 1+. In tumors with a Ki-67 index ≥ 14%, all tested miRNAs were underexpressed in BC with a high Allred PR score (6–8). In ER-and-PR–negative tumors, miR-22, miR-222, miR-181a, and miR-378a underexpression was associated with Ki-67 index > 35% (median value). MiR-19b and miR-22 underexpression could be a marker of lymph node metastasis in ER- and/or PR-positive tumors with HER2 IHC score 0. Thus, the association of miR-19b, miR-22, miR-222, miR-378a, and miR-181a levels with BC characteristics is influenced by the status of tumor ER, PR, HER2, and Ki-67.
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Mar-Aguilar, Fermín, Jorge A. Mendoza-Ramírez, Ismael Malagón-Santiago, Perla K. Espino-Silva, Sandra K. Santuario-Facio, Pablo Ruiz-Flores, Cristina Rodríguez-Padilla, and Diana Reséndez-Pérez. "Serum Circulating microRNA Profiling for Identification of Potential Breast Cancer Biomarkers." Disease Markers 34, no. 3 (2013): 163–69. http://dx.doi.org/10.1155/2013/259454.
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MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules that can regulate gene expression, thereby affecting crucial processes in cancer development. miRNAs offer great potential as biomarkers for cancer detection because of their remarkable stability in blood and their characteristic expression in different diseases. We investigated whether quantitative RT-PCR miRNA profiling on serum could discriminate between breast cancer patients and healthy controls. We performed miRNA profiling on serum from breast cancer patients, followed by construction of ROC (Receiver Operating Characteristic) curves to determine the sensitivity and specificity of the assay. We found that seven miRNAs (miR-10b, miR-21, miR-125b, miR-145, miR-155 miR-191 and miR-382) had different expression patterns in serum of breast cancer patients compared to healthy controls. ROC curve analyses revealed that three serum miRNAs could be valuable biomarkers for distinguishing BC from normal controls. Additionally, a combination of ROC curve analyses of miR-145, miR-155 and miR-382 showed better sensitivity and specificity of our assay. miRNA profiling in serum has potential as a novel method for breast cancer detection in the Mexican population.
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Bappayya, Shaneel, Hamish Clydesdale, and Simon Tsao. "Circulating Tumour Cells and MicroRNA in Thyroid Cancer - a Systematic Review." Journal of the Endocrine Society 5, Supplement_1 (May 1, 2021): A858. http://dx.doi.org/10.1210/jendso/bvab048.1752.
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Abstract Background: Thyroid cancer (TC) is the most common endocrine malignancy worldwide. Currently available circulating biomarkers such as thyroglobulin and calcitonin present severe limitations to the diagnosis and management of often difficult-to-diagnose lesions. There is increasing interest in the utility of circulating tumour cells (CTCs) and microRNAs to diagnose and optimise the management of patients with TC. Methods: In this study, we undertake a systematic review to gain a better understanding of the utility of CTCs and microRNAs in the diagnosis and management of patients with TC. A systematic review of the literature was performed by searching electronic bibliographic databases MEDLINE, EMBASE, SCOPUS and Web of Science. Studies which measured CTCs or microRNA levels in peripheral blood from TC patients were included. Review articles, conference abstracts, and foreign language papers were excluded. Results: There were 238 records screened for inclusion. Full texts of 47 articles were reviewed and included for qualitative analysis. CTCs demonstrated value in disease monitoring by distinguishing between disease recurrence and remission in patients with papillary thyroid cancer (PTC) and differentiated thyroid cancer (DTC). Higher CTC counts were associated with poorer progression free survival. This is consistent with CTC studies in other cancers such as breast and colorectal. A total of 31 microRNA biomarker candidates were investigated in studies reviewed. Circulating miR-222, miR-221 and miR-146b were most commonly increased in patients with PTC compared to benign nodules and healthy controls, and were associated with poorer prognostic factors including extrathyroidal invasion and metastatic lymph nodes. Circulating miR-222-3p and miR-17-5p demonstrated discriminatory power between medullary thyroid cancer (MTC) and benign nodules and healthy controls. Conclusion: CTCs demonstrate a promising avenue for disease monitoring and detection of local and distant recurrence in patients with DTC. Several microRNA candidates demonstrate value in diagnosis of PTC and MTC. There is a large degree of heterogeneity in studies assessing the utility of microRNA biomarker candidates. Further studies are warranted to ascertain the value of circulating microRNA in disease monitoring and prognosis.
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Filippova, Elena A., Marina V. Fridman, Alexey M. Burdennyy, Vitaly I. Loginov, Irina V. Pronina, Svetlana S. Lukina, Alexey A. Dmitriev, and Eleonora A. Braga. "Long Noncoding RNA GAS5 in Breast Cancer: Epigenetic Mechanisms and Biological Functions." International Journal of Molecular Sciences 22, no. 13 (June 24, 2021): 6810. http://dx.doi.org/10.3390/ijms22136810.
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Long noncoding RNAs (lncRNAs) have been identified as contributors to the development and progression of cancer through various functions and mechanisms. LncRNA GAS5 is downregulated in multiple cancers and acts as a tumor suppressor in breast cancer. GAS5 interacts with various proteins (e.g., E2F1, EZH2, and YAP), DNA (e.g., the insulin receptor promoter), and various microRNAs (miRNAs). In breast cancer, GAS5 binds with miR-21, miR-222, miR-221-3p, miR-196a-5p, and miR-378a-5p that indicates the presence of several elements for miRNA binding (MREs) in GAS5. Mediated by the listed miRNAs, GAS5 is involved in the upregulation of a number of mRNAs of suppressor proteins such as PTEN, PDCD4, DKK2, FOXO1, and SUFU. Furthermore, the aberrant promoter methylation is involved in the regulation of GAS5 gene expression in triple-negative breast cancer and some other carcinomas. GAS5 can stimulate apoptosis in breast cancer via diverse pathways, including cell death receptors and mitochondrial signaling pathways. GAS5 is also a key player in the regulation of some crucial signal pathways in breast cancer, such as PI3K/AKT/mTOR, Wnt/β-catenin, and NF-κB signaling. Through epigenetic and other mechanisms, GAS5 can increase sensitivity to multiple drugs and improve prognosis. GAS5 is thus a promising target in the treatment of breast cancer patients.
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Chu, Jiahui, Yongfei Li, Xuemei Fan, Jingjing Ma, Jun Li, Guangping Lu, Yanhong Zhang, et al. "MiR-4319 Suppress the Malignancy of Triple-Negative Breast Cancer by Regulating Self-Renewal and Tumorigenesis of Stem Cells." Cellular Physiology and Biochemistry 48, no. 2 (2018): 593–604. http://dx.doi.org/10.1159/000491888.
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Background/Aims: High levels of cancer stem cells (CSCs) in patients with triple-negative breast cancer (TNBC) correlate with risk of poor clinical outcome and possibly contribute to chemoresistance and metastasis in patients with highly malignant TNBC. Aberrant microRNA expression is associated with the dysfunction of self-renewal and proliferation in cancer stem cells, while there is little information about the TNBC-specific microRNAs in regulating CSC ability. Methods: Solexa deep sequencing was performed to detect the expression levels of TNBC or non-TNBC stem cells (CSCs) microRNAs. Mammosphere formation assay, qRT-PCR and the xenograft model in nude mice were performed. Bioinformatic analysis and microarray were used to select the target gene, and luciferase reporter assays were used to confirm the binding sites. Results: Solexa sequencing data exhibited differential expression of 193 microRNAs between TNBC and non-TNBC stem cells. The gene ontology analysis and pathways analyses showed that genes were involved in the maintenance of stemness. MiR-4319 could suppress the self-renewal and formation of tumorspheres in TNBC CSCs through E2F2, and also inhibited tumor initiation and metastasis in vivo. Moreover, increased E2F2 could reverse the effect of miR-4319 on the self-renewal in TNBC CSCs. Conclusions: MiR-4319 suppresses the malignancy of TNBC by regulating self-renewal and tumorigenesis of stem cells and might be a remarkable prognostic factor or therapeutic target for patients with TNBC.
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Markou, Athina, George M. Yousef, Efstathios Stathopoulos, Vassilis Georgoulias, and Evi Lianidou. "Prognostic Significance of Metastasis-Related MicroRNAs in Early Breast Cancer Patients with a Long Follow-up." Clinical Chemistry 60, no. 1 (January 1, 2014): 197–205. http://dx.doi.org/10.1373/clinchem.2013.210542.
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Abstract BACKGROUND Stability of microRNAs (miRNAs) in formalin-fixed paraffin-embedded (FFPE) tissues enables their reliable analysis in archived FFPE tissue samples, which are an invaluable source for the evaluation of novel biomarkers. Especially in breast cancer, for which late relapses occur in many cases, analysis of miRNAs in FFPE tissues holds great potential, because it can lead to the discovery of novel biomarkers suitable for future routine clinical diagnostics for breast cancer. We investigated the prognostic significance of 6 metastasis-related miRNAs that can critically regulate various stages of migration and invasion and play critical roles in the multistep metastatic process. METHODS We quantified the expression of 6 mature miRNAs (namely miR-21, miR-205, miR-10b, miR-210, miR-335, and let-7a) by reverse-transcription quantitative PCR in FFPE tissues of 84 patients with early breast cancer and a long follow-up and 13 cancer-free breast tissue FFPE samples that were used as the control group. We further correlated individual miRNA over- or underexpression with the disease-free interval (DFI) and overall survival (OS). RESULTS Univariate analysis revealed that both miR-21 and miR-205 were significantly associated with DFI and only miR-205 with OS. Multivariate analysis demonstrated that miR-205 and miR-21 were independent factors associated with early disease relapse, whereas only miR-205 overexpression was associated with OS. CONCLUSIONS Our results clearly indicate that deregulation of metastasis-associated miRNAs in primary tumors is associated with clinical outcome in patients with early breast cancer and can differentiate patients with higher risk in well-characterized subgroups.
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Liu, Yan, Ai Zhang, Ping-Ping Bao, Li Lin, Yina Wang, Haijian Wu, Xiao-Ou Shu, Aiguo Liu, and Qiuyin Cai. "MicroRNA-374b inhibits breast cancer progression through regulating CCND1 and TGFA genes." Carcinogenesis 42, no. 4 (January 22, 2021): 528–36. http://dx.doi.org/10.1093/carcin/bgab005.
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Abstract Emerging evidence indicates that microRNAs (miRNAs) play a critical role in breast cancer development. We recently reported that a higher expression of miR-374b in tumor tissues was associated with a better disease-free survival of triple-negative breast cancer (TNBC). However, the functional significance and molecular mechanisms underlying the role of miR-374b in breast cancer are largely unknown. In this current study, we evaluated the biological functions and potential mechanisms of miR-374b in both TNBC and non-TNBC. We found that miR-374b was significantly downregulated in breast cancer tissues, compared to adjacent tissues. MiR-374b levels were also lower in breast cancer cell lines, as compared to breast epithelial cells. In vitro and in vivo studies demonstrated that miR-374b modulates the malignant behavior of breast cancer cells, such as cell proliferation in 2D and 3D, cell invasion ability, colony-forming ability and tumor growth in mice. By using bioinformatics tools, we predicted that miR-374b plays a role in breast cancer cells through negatively regulating cyclin D1 (CCND1) and transforming growth factor alpha (TGFA). We further confirmed that CCND1 and TGFA contribute to the malignant behavior of breast cancer cells in vitro and in vivo. Our rescue experiments showed that overexpressing CCND1 or TGFA reverses the phenotypes caused by miR-374b overexpression. Taken together, our studies suggest that miR-374b modulates malignant behavior of breast cancer cells by negatively regulating CCND1 and TGFA genes. The newly identified miR-374b-mediated CCND1 and TGFA gene silencing may facilitate a better understanding of the molecular mechanisms of breast cancer progression.
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Yang, Chun, Seyed Nasrollah Tabatabaei, Xiangyan Ruan, and Pierre Hardy. "The Dual Regulatory Role of MiR-181a in Breast Cancer." Cellular Physiology and Biochemistry 44, no. 3 (2017): 843–56. http://dx.doi.org/10.1159/000485351.
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MicroRNAs (miRNAs) are a family of highly conserved noncoding single˗stranded RNA molecules of 21 to 25 nucleotides. miRNAs silence their cognate target genes at the post-transcriptional level and have been shown to have important roles in oncogenesis, invasion, and metastasis via epigenetic post-transcriptional gene regulation. Recent evidence indicates that the expression of miR-181a is altered in breast tumor tissue and in the serum of patients with breast cancer. However, there are several contradicting findings that challenge the biological significance of miR-181a in tumor development and metastasis. In fact, some studies have implicated miR-181a in regulating breast cancer gene expression. Here we summarize the current literature demonstrating established links between miR-181a and human breast cancer with a focus on recently identified mechanisms of action. This review also aims to explore the potential of miR-181a as a diagnostic and/or prognostic biomarker for breast cancer and to discuss the contradicting data regarding its targeting therapeutics and the associated challenges.
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Ibrahim, Alaa M., Mahmoud M. Said, Amany M. Hilal, Amina M. Medhat, and Ibrahim M. Abd Elsalam. "Candidate circulating microRNAs as potential diagnostic and predictive biomarkers for the monitoring of locally advanced breast cancer patients." Tumor Biology 42, no. 10 (October 2020): 101042832096381. http://dx.doi.org/10.1177/1010428320963811.
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This study aimed at investigating the expression of candidate microRNAs (miRs), at initial diagnosis, during neoadjuvant chemotherapy, and after the tumor resection in locally advanced breast cancer patients. Plasma samples were collected from locally advanced breast cancer patients (n = 30) and healthy subjects (n = 20) for the detection of candidate miRs’ expression using the real-time quantitative polymerase chain reaction. At initial locally advanced breast cancer diagnosis, the expression of miR-21, miR-181a, and miR-10b was significantly increased, whereas that of miR-145 and let-7a was significantly decreased, compared to the healthy individuals. The diagnostic accuracy of miR-21 was superior to both carcinoembryonic antigen and carcinoma antigen 15-3 as diagnostic biomarkers for locally advanced breast cancer. By the end of the treatment, the expression of altered miRs rebound to control values. The expression levels of candidate plasma miRs are useful diagnostic biomarkers, as well as monitoring a proper response for locally advanced breast cancer patients to the treatment. Furthermore, miR-10b and miR-21 can be considered as predictive biomarkers for progression-free survival.
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Zhang, Guochen, Junlan Wang, Ruilin Zheng, Beibei Song, Li Huang, Yujiang Liu, Yating Hao, and Xiangdong Bai. "MiR-133 Targets YES1 and Inhibits the Growth of Triple-Negative Breast Cancer Cells." Technology in Cancer Research & Treatment 19 (January 1, 2020): 153303382092701. http://dx.doi.org/10.1177/1533033820927011.
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Triple-negative breast cancer shows worse outcome compared with other subtypes of breast cancer. The discovery of dysregulated microRNAs and their roles in the progression of triple-negative breast cancer provide novel strategies for the treatment of patients with triple-negative breast cancer. In this study, we identified the significant reduction of miR-133 in triple-negative breast cancer tissues and cell lines. Ectopic overexpression of miR-133 suppressed the proliferation, colony formation, and upregulated the apoptosis of triple-negative breast cancer cells. Mechanism study revealed that the YES Proto-Oncogene 1 was a target of miR-133. miR-133 bound the 3′-untranslated region of YES Proto-Oncogene 1 and decreased the level of YES Proto-Oncogene 1 in triple-negative breast cancer cells. Consistent with miR-133 downregulation, YES1 was significantly increased in triple-negative breast cancer, which was inversely correlated with the level of miR-133. Restoration of YES Proto-Oncogene 1 attenuated the inhibitory effects of miR-133 on the proliferation and colony formation of triple-negative breast cancer cells. Consistent with the decreased expression of YES Proto-Oncogene 1, overexpression of miR-133 suppressed the phosphorylation of YAP1 in triple-negative breast cancer cells. Our results provided novel evidence for the role of miR-133/YES1 axis in the development of triple-negative breast cancer, which indicated miR-133 might be a potential therapeutic strategy for triple-negative breast cancer.
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Jeong, Jae-Hwan, Soo Jung Lee, Jeeyeon Lee, Jin Hyang Jung, Ho Yong Park, Ji-young Park, Seung Hee Kang, Yee Soo Chae, and Jong Gwang Kim. "Effect of MiR-137 and MiR-496 on Del-1 and triple negative breast cancer progression." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e23058-e23058. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e23058.
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e23058 Background: Although Del-1 was recently proposed as a new biomarker for early breast cancer in our previous studies, the mechanisms of Del-1 expression are barely understood. In the current study, we selected two microRNAs (miR-137 and - 496), potentially affecting Del-1 expression in breast cancer and examined their impact on Del-1 expression in a variety of breast cancer cell lines to identify their potential role in Del-1 expression and thereby breast cancer development or progression. . Methods: Del-1 mRNA and miR-137/– 496 levels were measured by qRT-PCR among breast epithelial (MCF10A) and cancer cells (MDA-MB-231, MCF7, SK-BR3 and T-47D). The effects of miR-137/– 496 on cell proliferation and invasion were detected using MTT, wound healing and Transwell assays. Furthermore, luciferase reporter assay was used to identify the direct regulation of Del-1 by miR-137 or – 496 in MDA-MB-231 cells. Plus, we analyzed the expressions of miR-137 or – 496 and Del-1 mRNA from 20 patients with triple negative early breast cancer. Results: miR-137 and – 496 levels were low in all breast cancer cell lines. As Del-1 mRNA expression was remarkably higher in MDA-MB-231 compared to the other breast cancer cell lines, further functional analyses were done with MDA-MB-231 representing triple negative breast cancer subtype. Both miR-137 and miR-496 were revealed to directly bind at the 3’-UTR of Del-1. Del-1 by Luciferase reporter assay and Del-1 expression was upregulated by inhibitors and reversed by both mimics of both miR-137 and miR-496. Furthermore, both miR-137 and miR-496 were also demonstrated to inhibit cell proliferation, migration and invasion of MDA-MB-231, suggesting that these miRNAs affect cancer progression via Del-1. MiR-137 and miR-496 were remarkably down-regulated in 7 out of 12 triple negative breast cancer tissues, in particular with high Ki67 and high histologic grade. Conclusions: Although Del-1 was recently introduced as a new biomarker for triple negative breast cancer, the mechanisms of Del-1 expression were barely identified. The current study firstly demonstrated that microRNA 137 and 496 are involved in Del-1 regulation by binding at Del-1 gene, affecting cancer progression by altering Del-1 expression.