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Journal articles on the topic 'Androgen receptor amplification'

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Published: 4 June 2021

Last updated: 15 February 2022

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Ryan, Charles J., and Donald J. Tindall. "Androgen Receptor Rediscovered: The New Biology and Targeting the Androgen Receptor Therapeutically." Journal of Clinical Oncology 29, no. 27 (2011): 3651–58. http://dx.doi.org/10.1200/jco.2011.35.2005.

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Discoveries over the past decade suggest that castration-resistant prostate cancer (CRPC) is sensitive, but not resistant to, further manipulation of the androgen–androgen receptor (AR) axis. Several new therapies that target this axis have demonstrated clinical activity. In this article, preclinical and clinical findings occurring in the field of AR-targeted therapies are reviewed. Reviews of scientific and clinical development are divided into those occurring prereceptor (androgen production and conversion) and at the level of the receptor (AR aberrations and therapies targeting AR directly). Intracrine androgen production and AR amplification, among others, are among the principal aberrancies driving CRPC growth. Phase III data with abiraterone acetate and phase II data with MDV-3100, along with other similar therapies, confirm for the clinician that the scientific findings related to persistent AR signaling in a castrate milieu can be harnessed to produce significant clinical benefit for patients with the disease. Studies aimed at optimizing the timing of their use and exploring the mechanisms of resistance to these therapies are under way. The clinical success of therapies that directly target androgen synthesis as well as the most common aberrancies of the AR confirm that prostate cancer retains dependence on AR signaling, even in the castrate state.

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Ledet, Elisa Marie, Patrick Cotogno, Whitley Hatton, et al. "Androgen receptor cfDNA longitudinal mutational analysis in metastatic castrate-resistant prostate cancer." Journal of Clinical Oncology 38, no. 6_suppl (2020): 197. http://dx.doi.org/10.1200/jco.2020.38.6_suppl.197.

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197 Background: Androgen receptor (AR) mutations commonly occur in metastatic castrate resistant prostate cancer (mCRPC). Methods: Circulating tumor DNA (ctDNA) data were obtained from Guardant 360 assays throughout the clinical course of mCRPC patients (pts). Retrospective analysis for any pt with ≥ 3 Guardant assays at least 4 weeks apart were reviewed. Patients must have at least 1 AR mutation or amplification to qualify for inclusion. Statistical analyses, including chi-sq and longitudinal analyses, were conducted. Results: Of the 259 patients with Guardant testing, a total of 88 patients had at least 3 Guardant tests; of these, 59 (67%) had at least one AR alteration. Patients had a median of 4 Guardant assays (range 3-10). Patients with AR amplification, AR mutation or both were identified (23, 20, 16 respectively). The most common and clinically relevant AR mutations found alone or in combination with amplification were T878A (22%), L702H(19%), W742C (19%), and H875Y (10%). These particular functional AR mutations occurred alone in 16 patients. Only 3 patients had neither amplification nor common AR mutation. 17/59 patients were found to have at least one common AR mutation and amplification at some point (on same or different Guardant). One patient had seven different AR mutations with no amplification and two other patients had 3 AR mutations. Remainder of patients had either AR amplification or ≤ 2 alternative mutations. Patients with an AR amplification were 0.1138x (95% Cl 0.0289 - 0.4491) significantly less likely of having a common known functional mutation (p <0.002) at any point. Conclusions: Patients with the most frequently identified known functional AR mutations are less likely to have AR amplification in pts with mCRPC; these common AR mutations have been shown to be associated with resistance to 2nd generation androgen deprivation. Further clinical correlation between treatment regimen and %cfDNA of these and other non-AR driver mutations is planned.

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Han, G. Celine, Justin Hwang, Stephanie A. M. Wankowicz, et al. "Genomic Resistance Patterns to Second-Generation Androgen Blockade in Paired Tumor Biopsies of Metastatic Castration-Resistant Prostate Cancer." JCO Precision Oncology, no. 1 (November 2017): 1–11. http://dx.doi.org/10.1200/po.17.00140.

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Purpose Patients with castration-resistant prostate cancer (CRPC) receive second-generation androgen-deprivation therapy, but frequently experience relapse or do not respond. Understanding the genetic mechanisms of resistance will help to identify strategies and biomarkers that are essential for the next line of therapy. Patients and Methods We analyzed whole exomes of patient-matched pre- and post-treatment tumors from patients with CRPC. These patients had received the secondary androgen-deprivation therapy agent, abiraterone, which suppresses androgens to below castration levels, or enzalutamide, which competitively inhibits the key androgen signaling effector, androgen receptor. Results We observed that abiraterone-resistant tumors harbored alterations in AR and MYC, whereas enzalutamide-resistant tumors gained alterations in cell-cycle pathway genes, such as mutation in cyclin-dependent kinase N2A ( CDKN2A) or amplification of CDK6. Experimentally, overexpressing cell-cycle kinases promoted enzalutamide resistance in androgen-sensitive LnCAP cells that was mitigated via CDK4/6 blockade—palbociclib and ribociclib. Conclusion CDK4/6-mediated resistance observed in preclinical experiments suggests that CDK4/6 amplifications may sufficiently promote enzalutamide resistance in CRPC, and that these patients may respond to palbociclib or ribociclib. The overall observations suggest that, in genomically selected advanced CRPC, clinical strategies against abiraterone- or enzalutamide-resistant tumors may require treatment strategies that are tailored to the resistance mechanisms that are specific to those patient subpopulations.

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Jernberg, Emma, Anders Bergh, and Pernilla Wikström. "Clinical relevance of androgen receptor alterations in prostate cancer." Endocrine Connections 6, no. 8 (2017): R146—R161. http://dx.doi.org/10.1530/ec-17-0118.

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Prostate cancer (PC) remains a leading cause of cancer-related deaths among men worldwide, despite continuously improved treatment strategies. Patients with metastatic disease are treated by androgen deprivation therapy (ADT) that with time results in the development of castration-resistant prostate cancer (CRPC) usually established as metastases within bone tissue. The androgen receptor (AR) transcription factor is the main driver of CRPC development and of acquired resistance to drugs given for treatment of CRPC, while a minority of patients have CRPC that is non-AR driven. Molecular mechanisms behind epithelial AR reactivation in CRPC include AR gene amplification and overexpression, AR mutations, expression of constitutively active AR variants, intra-tumoural and adrenal androgen synthesis and promiscuous AR activation by other factors. This review will summarize AR alterations of clinical relevance for patients with CRPC, with focus on constitutively active AR variants, their possible association with AR amplification and structural rearrangements as well as their ability to predict patient resistance to AR targeting drugs. The review will also discuss AR signalling in the tumour microenvironment and its possible relevance for metastatic growth and therapy.

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Suárez-Quian, Carlos A., Francisco Martínez-García, Manuel Nistal, and Javier Regadera. "Androgen Receptor Distribution in Adult Human Testis1." Journal of Clinical Endocrinology & Metabolism 84, no. 1 (1999): 350–58. http://dx.doi.org/10.1210/jcem.84.1.5410.

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The distribution of the androgen receptor (AR) in archival human testes was determined immunocytochemically using an affinity-purified peptide-specific rabbit antibody, PG21, and employing a modified biotin-streptavidin-immunoperoxidase method that incorporated a biotin amplification step. In combination with microwave epitope retrieval, the biotin amplification step increased the sensitivity of the immunostaining assay approximately 20-fold. Thus, the useful range at which PG21 rendered a robust, specific immunostaining signal without also increasing nonspecific background was extended dramatically. Broadening the useful range of the PG21 antibody made it possible to resolve the relative amounts of immunopositive AR in different cell types of the human testis. At a high PG21 concentration, for example, all AR-positive cells exhibited a robust immunostaining intensity, but it was not possible to distinguish between nuclei exhibiting either high or moderate immunostaining intensities. In contrast, as the concentration of PG21 was decreased, distinct populations of testicular cells exhibited differential AR immunostaining intensities in their nuclei. AR immunostaining of Sertoli cell nuclei was present at low PG21 concentrations at which no immunostaining of peritubular myoid cells or Leydig cells could be detected. In turn, AR immunostaining of peritubular myoid cells was detected at PG21 concentrations that did not immunostain Leydig cells. Moreover, within the seminiferous epithelium, Sertoli cell nuclear AR staining intensity was less at stages V and VI of the cycle of the seminiferous epithelium than that at stage III, and stage III staining intensity was greater than that at stages I and II. This AR immunostaining pattern in human Sertoli cell nuclei as a function of the cycle of the seminiferous epithelium is reminiscent of the pattern observed in rodent species. Finally, no AR immunostaining of germ cells was observed at any of the PG21 concentrations examined.

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Yao, Binbin, Sha Zhu, Xinyu Xu, Ninghan Feng, Yaping Tian, and Nandi Zhou. "Ultrasensitive detection of the androgen receptor through the recognition of an androgen receptor response element and hybridization chain amplification." Analyst 144, no. 6 (2019): 2179–85. http://dx.doi.org/10.1039/c9an00034h.

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Edwards, J., N. S. Krishna, R. Mukherjee, A. D. Watters, M. A. Underwood, and J. M. S. Bartlett. "Amplification of the androgen receptor may not explain the development of androgen-independent prostate cancer." BJU International 88, no. 6 (2001): 633–37. http://dx.doi.org/10.1046/j.1464-410x.2001.02350.x.

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&NA;. "Prostatic cancer develops resistance to androgen-deprivation therapy through amplification of the androgen receptor gene." Advances in Anatomic Pathology 2, no. 6 (1995): 405. http://dx.doi.org/10.1097/00125480-199511000-00035.

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Lamont, Kristin R., and Donald J. Tindall. "Minireview: Alternative Activation Pathways for the Androgen Receptor in Prostate Cancer." Molecular Endocrinology 25, no. 6 (2011): 897–907. http://dx.doi.org/10.1210/me.2010-0469.

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Abstract Advanced prostate tumors, which are androgen dependent, are often initially treated in the clinic with hormone ablation therapy, either through surgical castration or administration of small-molecule antiandrogens. Most tumors respond favorably to these treatments, exhibiting regression of the tumor, amelioration of symptoms, and a decrease of prostate-specific antigen in patient sera. However, with time, the majority of tumors recur in a more aggressive, castration-resistant (CR) phenotype. Currently, no effective treatment exists for this stage of the cancer, and patients ultimately succumb to metastatic disease. The androgen receptor (AR), which is a member of the nuclear hormone receptor superfamily of proteins, is the transcription factor that is responsible for mediating the effects of androgens upon target tissues, and it has been demonstrated to play a central role in the development and progression of prostate cancer. Despite CR tumor cells being able to continue to grow after hormonal therapy in which testosterone and dihydrotestosterone are markedly reduced, they still require the expression and activity of the AR. The AR can become transactivated in this low-androgen environment through a number of different mechanisms, including amplification and mutation of the receptor, cross talk with other signaling pathways, and altered regulation by coregulatory proteins. This review will summarize the most current data regarding non-ligand-mediated activation of the AR in prostate cancer cells. Developing work in this field aims to more clearly elucidate the signals that drive AR activity independently of androgens in CR disease so that better therapeutic targets can be developed for patients with this stage of highly aggressive prostate carcinoma.

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Becker, Matthias, Elke Martin, Jean Schneikert, Harald F. Krug, and Andrew C. B. Cato. "Cytoplasmic Localization and the Choice of Ligand Determine Aggregate Formation by Androgen Receptor with Amplified Polyglutamine Stretch." Journal of Cell Biology 149, no. 2 (2000): 255–62. http://dx.doi.org/10.1083/jcb.149.2.255.

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Polyglutamine tract expansion in androgen receptor is a recognized cause of spinal and bulbar muscular atrophy (SBMA), an X-linked motor neuronopathy. Similar mutations have been identified in proteins associated with other neurodegenerative diseases. Recent studies have shown that amplified polyglutamine repeat stretches form cellular aggregates that may be markers for these neurodegenerative diseases. Here we describe conditions that lead to aggregate formation by androgen receptor with polyglutamine stretch amplification. In transfection experiments, the mutant, compared with the wild-type receptor, was delayed in its cytoplasmic–nuclear translocation and formed large cytoplasmic aggregates in the presence of androgen. The cytoplasmic environment appears crucial for this aggregation, since retention of both the wild-type and mutant receptors in this cellular compartment by the deletion of their nuclear localization signals resulted in massive aggregation. Conversely, rapid nuclear transport of both receptors brought about by deletion of their ligand binding domains did not result in aggregate formation. However, androgen antagonists that altered the conformation of the ligand binding domain and promoted varying rates of cytoplasmic–nuclear translocation all inhibited aggregate formation. This demonstrates that in addition to the cytoplasmic localization, a distinct contribution of the ligand binding domain of the receptor is necessary for the aggregation. The finding that antiandrogens inhibit aggregate formation may provide the basis for in vivo determination of the role of these structures in SBMA.

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FORD, O. HARRIS, CHRISTOPHER W. GREGORY, DESOK KIM, ANDREW B. SMITHERMAN, and JAMES L. MOHLER. "Androgen Receptor Gene Amplification and Protein Expression in Recurrent Prostate Cancer." Journal of Urology 170, no. 5 (2003): 1817–21. http://dx.doi.org/10.1097/01.ju.0000091873.09677.f4.

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Scher, Howard I., and Charles L. Sawyers. "Biology of Progressive, Castration-Resistant Prostate Cancer: Directed Therapies Targeting the Androgen-Receptor Signaling Axis." Journal of Clinical Oncology 23, no. 32 (2005): 8253–61. http://dx.doi.org/10.1200/jco.2005.03.4777.

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Prostate cancers that are progressing on medical and surgical therapies designed to ablate the action of androgens continue to express androgen receptor (AR) and to depend on signaling through the receptor for growth. A more clinically relevant classification of castration-resistant disease focuses on the mechanisms of receptor activation, which include (1) changes in the level of ligand(s) in tumor tissue; (2) increased levels of the protein due to gene amplification or altered mRNA expression; (3) activating mutations in the receptor that affect structure and function; (4) changes in coregulatory molecules including coactivators and corepressors; and (5) factors that lead to activation of the receptor independent of the level of ligand or receptor allowing kinase cross talk. From an AR perspective, the term “hormone refractory” is inappropriate. On the basis of this schema, we discuss strategies that are focused on the AR either directly or indirectly, as single agents or in combination, that are in clinical development.

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Du, Meijun, Chiang-Ching Huang, Winston Tan, Manish Kohli, and Liang Wang. "Multiplex Digital PCR to Detect Amplifications of Specific Androgen Receptor Loci in Cell-Free DNA for Prognosis of Metastatic Castration-Resistant Prostate Cancer." Cancers 12, no. 8 (2020): 2139. http://dx.doi.org/10.3390/cancers12082139.

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Amplification of androgen receptor (AR) is a common genomic event in metastatic castration-resistant prostate cancer (mCRPC). To evaluate the prognostic value of the amplifications of specific loci in the AR gene in cell-free DNA, we developed a multiplex digital PCR (dPCR) assay that targeted AR enhancer (AR-En), AR exon 1 (AR-E1), AR exon 8 (AR-E8) and OPHN1 (downstream of AR). We selected three relatively stable genes, C2orf16, FAM111B, and GRIA3, as reference controls for copy number normalization. One hundred and eight mCRPC patients were recruited to test the association of specific AR loci amplification with clinical outcome. Using a normalized ratio ≥ 1.92 as cutoff, amplification of AR-En, AR-E1, AR-E8 and OPHN1 was observed in 28, 25, 24 and 19 of 108 mCRPC patients, respectively. Among the 41 patients with AR region amplification, 9 (21.9%) showed amplification at all four selected regions and 15 (36.6%) showed amplification at AR-En, AR-E1, and AR-E8. Six (14.6%) patients showed independent AR-En amplification, while the remaining 3 (7.3%) demonstrated AR-E8 amplification only. Kaplan–Meier analysis showed overall survival’s association with the amplification of AR-En (p = 0.02, HR = 1.68 (1.07–2.65)), AR-E8 (p = 0.02, HR = 1.78 (1.08–2.92)) and AR-En-E8 (the combination of AR-En and AR-E8 (p = 0.009, HR = 1.77 (1.15–2.73)). Multivariate models that included AR-En-E8 amplification and clinical factors significantly improved prognostic performance (p = 0.0001). With further validation, the multiplex dPCR assay may assist in prognostication of mCRPC patients.

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Messner, Elisabeth A., Thomas M. Steele, Maria Malvina Tsamouri, et al. "The Androgen Receptor in Prostate Cancer: Effect of Structure, Ligands and Spliced Variants on Therapy." Biomedicines 8, no. 10 (2020): 422. http://dx.doi.org/10.3390/biomedicines8100422.

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The androgen receptor (AR) plays a predominant role in prostate cancer (PCa) pathology. It consists of an N-terminal domain (NTD), a DNA-binding domain (DBD), a hinge region (HR), and a ligand-binding domain (LBD) that binds androgens, including testosterone (T) and dihydrotestosterone (DHT). Ligand binding at the LBD promotes AR dimerization and translocation to the nucleus where the DBD binds target DNA. In PCa, AR signaling is perturbed by excessive androgen synthesis, AR amplification, mutation, or the formation of AR alternatively spliced variants (AR-V) that lack the LBD. Current therapies for advanced PCa include androgen synthesis inhibitors that suppress T and/or DHT synthesis, and AR inhibitors that prevent ligand binding at the LBD. However, AR mutations and AR-Vs render LBD-specific therapeutics ineffective. The DBD and NTD are novel targets for inhibition as both perform necessary roles in AR transcriptional activity and are less susceptible to AR alternative splicing compared to the LBD. DBD and NTD inhibition can potentially extend patient survival, improve quality of life, and overcome predominant mechanisms of resistance to current therapies. This review discusses various small molecule and other inhibitors developed against the DBD and NTD—and the current state of the available compounds in clinical development.

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Jain, Pallavi, Pier-Luc Clermont, Francis Desmeules, Amina Zoubeidi, Bertrand Neveu, and Frédéric Pouliot. "Development of a Transcriptional Amplification System Based on the PEG3 Promoter to Target Androgen Receptor-Positive and -Negative Prostate Cancer Cells." International Journal of Molecular Sciences 20, no. 1 (2019): 216. http://dx.doi.org/10.3390/ijms20010216.

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Localized prostate cancer (PCa) is often curable, whereas metastatic disease treated by castration inevitably progresses toward castration-resistant PCa (CRPC). Most CRPC treatments target androgen receptor (AR) signaling. However, not all CRPC cells rely on AR activity for survival and proliferation. With advances in immunotherapy and fluid biopsies for cancer management, expression systems specific for both AR-positive and -negative PCa are required for virus-based vaccines and cell imaging. To target both AR-responsive and non-responsive cells, we developed a three-step transcriptional amplification (3STA) system based on the progression elevated gene-3 (PEG3) promoter named PEG3AP1-3STA. Notably, we report on different genetic modifications that significantly improved PEG3 promoter’s strength in PCa cells. Adenoviruses incorporating PEG3 promoter with and without transcriptional amplification systems were generated. The potential of PEG3AP1-3STA to target PCa cells was then evaluated in vitro and in vivo in androgen-responsive and non-responsive PCa cell lines. PEG3AP1-3STA was shown to be active in all PCa cell lines and not regulated by androgens, and its activity was amplified 97-fold compared to that of a non-amplified promoter. The PEG3AP1-3STA system can thus be used to target advanced AR+ and AR− cells for imaging or immunovirotherapy in advanced PCa.

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Shiota, Masaki, Akira Yokomizo, and Seiji Naito. "Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target." Journal of Molecular Endocrinology 47, no. 1 (2011): R25—R41. http://dx.doi.org/10.1530/jme-11-0018.

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Few effective therapies exist for the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC may be caused by augmented androgen/androgen receptor (AR) signaling, generally involving AR overexpression. Aberrant androgen/AR signaling associated with AR overexpression also plays a key role in prostate carcinogenesis. Although AR overexpression could be attributed to gene amplification, only 10–20% of CRPCs exhibit AR gene amplification, and aberrant AR expression in the remaining instances of CRPC is thought to be attributed to transcriptional, translational, and post-translational mechanisms. Overexpression of AR at the protein level, as well as the mRNA level, has been found in CRPC, suggesting a key role for transcriptional regulation of AR expression. Since the analysis of the AR promoter region in the 1990s, several transcription factors have been reported to regulate AR transcription. In this review, we discuss the molecules involved in the control of AR gene expression, with emphasis on its transcriptional control by transcription factors in prostate cancer. We also consider the therapeutic potential of targeting AR expression.

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Edwards, J., N. S. Krishna, K. M. Grigor, and J. M. S. Bartlett. "Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer." British Journal of Cancer 89, no. 3 (2003): 552–56. http://dx.doi.org/10.1038/sj.bjc.6601127.

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HAAPALA, K., T. KUUKASJARVI, E. HYYTINEN, I. RANTALA, H. HELIN, and P. KOIVISTO. "Androgen receptor amplification is associated with increased cell proliferation in prostate cancer☆." Human Pathology 38, no. 3 (2007): 474–78. http://dx.doi.org/10.1016/j.humpath.2006.09.008.

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Merson, S., Z. H. Yang, D. Brewer, et al. "Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer." British Journal of Cancer 110, no. 6 (2014): 1655–62. http://dx.doi.org/10.1038/bjc.2014.13.

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Roche, Philip J. R., Lenore K. Beitel, Rifat Khan, et al. "Demonstration of a plasmonic thermocycler for the amplification of human androgen receptor DNA." Analyst 137, no. 19 (2012): 4475. http://dx.doi.org/10.1039/c2an35692a.

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Madjunkova, S., A. Eftimov, V. Georgiev, D. Petrovski, A. Dimovski, and D. Plaseska-Karanfilska. "Cag Repeat Number in the Androgen Receptor Gene and Prostate Cancer." Balkan Journal of Medical Genetics 15, no. 1 (2012): 31–36. http://dx.doi.org/10.2478/v10034-012-0005-z.

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Cag Repeat Number in the Androgen Receptor Gene and Prostate CancerProstate cancer (PC) is the second leading cause of cancer deaths in men. The effects of androgens on prostatic tissue are mediated by the androgen receptor (AR) gene. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that numbers between 10 to 36 in the normal population. The length of the CAG repeats is inversely related to the transactivation function of the AR gene. There is controversy over association between short CAG repeat numbers in the AR gene and PC. This retrospective case-control study evaluates the possible effect of short CAG repeats on the AR gene in prostate cancer risk in Macedonian males. A total of 392 male subjects, 134 PC patients, 106 patients with benign prostatic hyperplasia (BPH) and 152 males from the general Macedonian population were enrolled in this study. The CAG repeat length was determined by fluorescent polymerase chain reaction (PCR) amplification of exon1 of the AR gene followed by capillary electrophoresis (CE) on a genetic analyzer. The mean repeat length in PC patients was 21.5 ±2.65, in controls 22.28 ±2.86 (p = 0.009) and in BPH patients 22.1 ±2.52 (p = 0.038). Short CAG repeats (<19) were found in 21.64% of PC patients vs. 9.43% in BPH patients (p = 0.0154). We also found an association of low Gleason score (<7) with short CAG repeat (<19) in PC patients (p = 0.0306), and no association between the age at diagnosis of PC and BPH and CAG repeat length. These results suggest that reduced CAG repeat length may be associated with increased prostate cancer risk in Macedonian men.

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Saraon, Punit, Keith Jarvi, and Eleftherios P. Diamandis. "Molecular Alterations during Progression of Prostate Cancer to Androgen Independence." Clinical Chemistry 57, no. 10 (2011): 1366–75. http://dx.doi.org/10.1373/clinchem.2011.165977.

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BACKGROUND Prostate cancer is the most commonly diagnosed cancer among men in North America and is a leading cause of death. Standard treatments include androgen deprivation therapy, which leads to improved clinical outcomes. However, over time, most tumors become androgen independent and no longer respond to hormonal therapies. Several mechanisms have been implicated in the progression of prostate cancer to androgen independence. CONTENT Most tumors that have become androgen independent still rely on androgen receptor (AR) signaling. Mechanisms that enhance AR signaling in androgen-depleted conditions include: AR gene amplification, AR mutations, changes in the balance of AR cofactors, increases in steroidogenic precursors, and activation via “outlaw” pathways. Along with AR signaling, various other AR-independent “bypass” pathways have been shown to operate aberrantly during androgen independence. Changes in the epigenetic signatures and microRNA concentrations have also been implicated in the development of androgen-independent prostate cancer. SUMMARY Understanding of the molecular mechanisms that lead to the development of androgen-independent prostate cancer will allow for improved therapeutic strategies that target key pathways and molecules that are essential for these cells to survive.

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Mackinnon, A. Craig, Benjamin C. Yan, Loren J. Joseph, and Hikmat A. Al-Ahmadie. "Molecular Biology Underlying the Clinical Heterogeneity of Prostate Cancer: An Update." Archives of Pathology & Laboratory Medicine 133, no. 7 (2009): 1033–40. http://dx.doi.org/10.5858/133.7.1033.

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Abstract Context.—Recent studies have uncovered a number of possible mechanisms by which prostate cancers can become resistant to systemic androgen deprivation, most involving androgen-independent reactivation of the androgen receptor. Genome-wide expression analysis with microarrays has identified a wide array of genes that are differentially expressed in metastatic prostate cancers compared to primary nonrecurrent tumors. Recently, recurrent gene fusions between TMPRSS2 and ETS family genes have been identified and extensively studied for their role in prostatic carcinoma. Objective.—To review the recent developments in the molecular biology of prostate cancer, including those pertaining to the androgen receptor and the newly identified TMPRSS2-related translocations. Data Sources.—Literature review and personal experience. Conclusions.—Prostatic adenocarcinoma is a heterogeneous group of neoplasms with a broad spectrum of pathologic and molecular characteristics and clinical behaviors. Numerous mechanisms contribute to the development of resistance to androgen ablation therapy, resulting in ligand-independent reactivation of the androgen receptor, including amplification, mutation, phosphorylation, and activation of coreceptors. Multiple translocations of members of the ETS oncogene family are present in approximately half of clinically localized prostate cancers. TMPRSS2:ERG gene rearrangement appears to be an early event in prostate cancer and is not observed in benign or hyperplastic prostatic epithelium. Duplication of TMPRSS2:ERG appears to predict a worse prognosis. The relationship between TMPRSS2:ERG gene rearrangement and other morphologic and prognostic parameters of prostate cancer is still unclear.

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Christensen, Bryce Raymon, Elisa Ledet, James Vu, et al. "Aberrations in androgen receptor ctDNA varies by race in metastatic castrate-resistant prostate cancer." Journal of Clinical Oncology 37, no. 7_suppl (2019): 247. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.247.

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247 Background: Characterization of circulating free DNA (ctDNA) may aid understanding of the pathophysiology of metastatic castrate resistant prostate cancer (mCRPC). The goal of this study was to evaluate and compare somatic alterations in ctDNA between African-American (AA) and Caucasian (C) mCRPC patients. Methods: 24 AA were retrospectively case-matched by prior treatment with 45 CA mCRPC; ctDNA was assessed with Guardant360 assay (Guardant Health, Redwood City, CA). Mutant allelic fraction, mutations, and gene amplification were compared. Results: Prior to testing, 6 AA pts and 12 CA pts had 0 lines of CRPC therapy, 7 AA pts and 10 CA pts had 1-2 lines, 5 AA and 17 CA had 3-4 lines, 5 AA and 2 CA had 5-6 lines, and 1 AA pt and 4 CA pts had >6 lines. The median Gleason score was 8, regardless of race. The median ctDNA mutant allelic fraction was 0.40% for AA pts and 0.60% for the CA pts. Mutations and/or amplifications in individually assessed genes are shown in the Table. No statistically significant differences were detected except for the androgen receptor (AR) gene where alterations (mutations and/or amplifications) were more frequent in AA as compared to C (p=0.04). Conclusions: AR alterations were more commonly detected in ctDNA in AA men as compared to C suggesting that AR driven pathophysiology may predominate in this setting. Additional analyses with a larger cohorts are warranted. Data from prospective trials in mCRPC using abiraterone/prednisone (George et al. LBA 5009, ASCO 2018) similarly suggest that mCRPC may be comparatively more AR driven in this racial setting. Alterations in ctDNA compared between AA and C men with mCRPC. [Table: see text]

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PAPP, A., P. SNYDER, M. SEDRA, M. GUIDA, and T. PRIOR. "Strategies for amplification of trinucleotide repeats: Optimization of fragile X and androgen receptor PCR." Molecular Diagnosis 1, no. 1 (1996): 59–64. http://dx.doi.org/10.1016/s1084-8592(96)70022-x.

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Koivisto, Pasi A., and Heikki J. Helin. "Androgen receptor gene amplification increases tissue PSA protein expression in hormone-refractory prostate carcinoma." Journal of Pathology 189, no. 2 (1999): 219–23. http://dx.doi.org/10.1002/(sici)1096-9896(199910)189:2<219::aid-path423>3.0.co;2-f.

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Brown, R. S. D., J. Edwards, A. Dogan, et al. "Amplification of the androgen receptor gene in bone metastases from hormone-refractory prostate cancer." Journal of Pathology 198, no. 2 (2002): 237–44. http://dx.doi.org/10.1002/path.1206.

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Koivisto, P. "Aneuploidy and rapid cell proliferation in recurrent prostate cancers with androgen receptor gene amplification." Prostate Cancer and Prostatic Diseases 1, no. 1 (1997): 21–25. http://dx.doi.org/10.1038/sj.pcan.4500200.

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Visakorpi, Tapio, Eija Hyytinen, Pasi Koivisto, et al. "In vivo amplification of the androgen receptor gene and progression of human prostate cancer." Nature Genetics 9, no. 4 (1995): 401–6. http://dx.doi.org/10.1038/ng0495-401.

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Gross, Mitchell E., David B. Agus, Tanya B. Dorff, et al. "Sequential monitoring of androgen receptor expression and copy number variation in castration-resistant prostate cancer (CRPC)." Journal of Clinical Oncology 31, no. 15_suppl (2013): 11047. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.11047.

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11047 Background: The high-definition circulating tumor cell (HD-CTC) assay provides for an enrichment-free approach to identify and characterize CTCs. Here, we utilized the HD-CTC assay to study androgen receptor (AR) expression combined with single-nucleus sequencing for genome-wide analysis of copy number variation (CNV) in sequential samples obtained from patients with CRPC treated with abiraterone acetate (AA). Methods: Patients were approached for participation in a study to provide peripheral blood at baseline, at 2-5 weeks, and at 9-12 weeks (or at progression). In each sample, 106cells (defined with a DAPI-intact nucleus) were quantitatively examined for the presence of cytokeratin and AR (CTCs) and CD45 (leukocytes). Initial results are available from 9 subjects treated with AA as standard of care. Results: At baseline, the median (range) CTC was 7.8 (1.1-57.2) cells/ml. Using a definition of AR positive (AR+) as >6 standard deviations over mean signal observed in leukocytes, the median (range) of AR+ and total CTCs observed at baseline were 3.1(0-33.8) and 7.8 (1.1-57.2) cells/ml, respectively. Detailed single-nucleus CNV analysis was performed in sequential samples in a single subject (Table). Complex genomic rearrangements were observed including AR amplification and 8p deletion in both AR+ and AR- negative (AR-) cells at baseline. During AA treatment, the frequency of AR+ CTCs decreased along with changes in the CNV pattern including loss of AR amplification. At 10 weeks, disease progression occurred coincident with re-emergence of an AR+ CTC population exhibiting AR amplification and a novel CNV pattern only distantly related to that of the baseline CTCs. While multiple complex abnormalities were noted, MYC amplification was observed at higher frequency in cells present at progression. Conclusions: Overall, our results demonstrate the feasibility of monitoring of CTCs for treatment emergent changes in protein which may be used to better monitoring and predict therapeutic responses in patients with metastatic cancer. [Table: see text]

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Fontana, Fabrizio, and Patrizia Limonta. "Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer." Cells 10, no. 5 (2021): 1133. http://dx.doi.org/10.3390/cells10051133.

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Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.

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Qazi, Maleeha, Katarzyna Jerzak, and Sharon Nofech-Mozes. "61. EXPRESSION OF ANDROGEN RECEPTOR IN BREAST CANCER BRAIN METASTASIS." Neuro-Oncology Advances 2, Supplement_2 (2020): ii13. http://dx.doi.org/10.1093/noajnl/vdaa073.049.

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Abstract INTRODUCTION Treatment options for women with breast cancer brain metastases (BrM) are generally limited to surgery and/or radiotherapy because most systemic therapies do not cross the blood-brain barrier. Androgen receptors (ARs) are frequently expressed in breast cancer and anti-androgenic therapies have been shown to penetrate the central nervous system. In this study, we analyzed the expression of AR in breast cancer BrM to identify patients who may benefit from anti-androgenic therapies. METHODS Consecutive BrM resected in our institution (July 1999-June 2013) were identified from the Anatomic Pathology departmental database. Cases that were signed out as breast origin given the available immunohistochemical profile and clinical history were included. A tissue microarray was constructed using 1 mm cores in triplicates and studied by immunohistochemistry for AR, ER, PR and HER2 (SP107, SP1, IE2, 4B5; Ventana Medical Systems, Tucson AZ, USA). HER2 gene amplification was determined by INFORM HER2 DNA and Chromosome 17 (both by Ventana Medical Systems, Tucson AZ, USA). Immunohistochemistry was used as a surrogate to determine intrinsic subtypes. RESULTS Among 61 breast cancer BrM with available tissue blocks, AR was expressed in 38 (62%) cases. Among BrMs of luminal A subtype (ER+, PR+/-, HER2-, Ki67&lt;16%), 50% expressed AR (n=1/2). Within the luminal B subtype (ER+, PR+/-), all 15 HER2+ BrM expressed AR (100%), while only 50% of HER2- BrM expressed AR (n=8/16). Among 14 BrM of HER2+ subtype (ER-, PR-), 71% expressed AR (n=10/14). Only 30% of triple negative BrM (ER-, PR-, HER2-) were AR+ (n=4/14). CONCLUSION Almost two-thirds of breast cancer BrM expressed AR. HER2+ luminal B and HER2+ subtypes were most likely to be AR+, while only 30% of triple negative BrM were AR+. Our data suggests that certain subtypes of breast cancer BrM are more likely to be AR+ and could serve as a potential therapeutic target.

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Calado, Rodrigo T., William T. Yewdell, Keisha L. Wilkerson, Joshua A. Regal, Sachiko Kajigaya, and Neal S. Young. "Sex Hormones Modulate the Length of Telomeres of Normal and Telomerase-Mutant Leukocytes through the Estrogen Receptor Pathway." Blood 108, no. 11 (2006): 182. http://dx.doi.org/10.1182/blood.v108.11.182.182.

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Abstract Telomeres are nucleoprotein complexes at chromosome ends that protect chromosomes from end-to-end fusion, damage, and recombination. Telomeres are eroded during cell division due to DNA polymerase’s inability to fully duplicate them. Immature cells, including hematopoietic stem cells, express telomerase to maintain telomere lengths. Mutations in genes encoding the telomerase complex (TERT, coding for the reverse transcriptase, and TERC, coding for the RNA component) are associated with constitutional and acquired aplastic anemia, causing low telomerase activity, short telomeres, and a reduced stem cell compartment. Bone marrow failure in telomerase-mutated patients often responds to androgen therapy, but the mechanism of action is unknown. We investigated whether sex steroids modulated telomerase expression and function in hematopoietic cells from healthy subjects and individuals carrying TERT mutations. Peripheral blood lymphocytes were cultured for two days in phenol-free RPMI 1640 supplemented with charcoal-treated 10% fetal bovine serum containing interleukin-2 and phycohemagglutinin in the presence or absence of methyltrienolone (R1881), 19-nortestosterone-17 decanoate (19-NT), 6-hydroxy-testosterone (6-HT), estradiol (E2), and/or tamoxifen, an estrogen antagonist, and/or letrozole, an aromatase inhibitor. Telomerase activity was measured by the telomeric repeat amplification protocol (TRAP) assay, and TERT expression by Real Time PCR. Both androgens and E2 stimulated telomerase activity in lymphocytes from normal subjects in a dose-dependent fashion that correlated to higher TERT mRNA levels; tamoxifen abolished sex steroid effects on telomerase function, while letrozole abrogated androgen from up-regulating telomerase in lymphocytes, indicating that sex steroids stimulate TERT expression through the estrogen receptor, which may interact with the estrogen receptor elements present in the promoter region of the TERT gene. As the PI3-K/Akt pathway has been implicated in the sex steroid-dependent activation of telomerase, we tested if this pathway was also activated in lymphocytes. In both immunoblot and flow cytometry analysis, we failed to observe any Akt phosphorylation induced by sex hormones, making it unlikely that this pathway plays a role in androgen-mediated telomerase activation in lymphocytes. We also addressed the effects of androgens of normal bone marrow CD34+ cells, which were purified in immunomagnetic columns and cultured in long-term liquid media, and R1881 also stimulated telomerase in normal marrow CD34+ cells. Peripheral blood lymphocytes from three TERT mutation healthy carriers were also cultured in the presence of androgens. As expected, TERT mutant cells had low baseline telomerase activity, which was restored to normal levels by R1881. These results indicate that sex steroids can modulate TERT expression and telomerase activity in hematopoietic cells signaling through estrogen receptors, and they can partially restore telomerase activity in TERT mutation carriers in vitro. Our findings provide a mechanism for androgen therapy in patients with either acquired or constitutional marrow failure caused by defects in telomere repair. These results also have implications in the physiological variation of telomere shortening, since telomere length of women during fertile age is stable, and hormone replacement therapy decreases the rate of telomere shortening in postmenopausal women.

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Doane, A. S., M. Danso, P. Lal, et al. "Distinct PIK3CA mutation profiles in estrogen receptor (ER) negative breast cancer (BC) subsets." Journal of Clinical Oncology 24, no. 18_suppl (2006): 540. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.540.

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540 Background: ER negative, progesterone receptor (PR) negative BC is clinically heterogeneous and underlying biology may be complex. We have identified two primary subtypes of ER(-)/PR(-) BC based on genome-wide molecular analysis (Doane et al., 2005, Oncogene, In Press), however the biological mechanisms underlying these molecular differences are not known. Methods: We performed genome-wide expression analysis of 99 primary BC samples and 13 BC cell lines. Total RNA was extracted and hybridized to Affymetrix HG-U133 oligonucleotide microarrays. Unsupervised and supervised analyses were used to investigate gene expression profiles. Predictive models were developed using a supervised k-nearest neighbor technique. Samples were further characterized by immunohistochemistry (IHC) for selected gene products, and HER2 status was determined by IHC and FISH. PIK3CA exons 9 and 20 were sequenced by RT-PCR amplification, direct sequencing, and restriction enzyme digest. Results: Genes differentially expressed between ER(-)/PR(-) subsets (designated class A and B) included SPDEF, ALCAM, AR, and FGFR4 (p<0.0001). Further study revealed a significant association with class A and the PIK3CA A3140G:H1047R activating mutation among ER(-)/PR(-) BC (p=0.012). HER2 status (gene amplification or 3+ IHC) was not significantly associated with this subtype (p=0.33). MDA-MB-453 corresponded to class A according to molecular profile and PIK3CA mutation status. This cell line demonstrated a proliferative response to androgen (A) in an androgen receptor (AR) dependent and ER-independent manner. In addition the A-induced transcriptional program of MDA-MB-453 significantly overlapped the molecular signature of ER(-)/PR(-) class A human BC (p<0.0001). Conclusion: Hormonal signaling through the AR may be significantly different in ER(-)/PR(-) molecular subsets. Enhanced AR signaling may be due to cooperation with growth factor signaling through PI3K. The potential molecular crosstalk between activated PI3K and the androgen signaling pathway provides therapeutic opportunities and deserves further study. No significant financial relationships to disclose.

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Kubota, Y. K., S. H. Hatakeyama, T. O. Okamoto, et al. "Prognostic significance of cell-free DNA and androgen receptor amplification in castration-resistant prostate cancer." European Urology 79 (June 2021): S599. http://dx.doi.org/10.1016/s0302-2838(21)00813-7.

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Plaseski, T., P. Noveski, C. Dimitrovski, B. Kocevska, G. Efremov, and D. Plaseska-Karanfilska. "Cag Repeat Number in Androgen Receptor Gene and Male Infertility." Balkan Journal of Medical Genetics 10, no. 1 (2007): 19–24. http://dx.doi.org/10.2478/v10034-007-0003-8.

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Cag Repeat Number in Androgen Receptor Gene and Male InfertilityAndrogens are essential for male sexual development and for fertility. They exert their action through the androgen receptor (AR), a ligandactivated transcription factor. The 5' end of exon 1 of the AR gene includes a polymorphic CAG triplet repeat that varies in number between 10 to 36 in the normal population. There is controversy over an association between high CAG repeat numbers in the AR gene and male infertility. We have evaluated the possible effect of long CAG repeats in the AR on infertility in men from the Republic of Macedonia (R. Macedonia). A group of 222 infertile/subfertile males with different sperm counts and a control group of 152 proven fathers were studied. The CAG repeat number was determined by fluorescent polymerase chain reaction (PCR) amplification of exon 1 of the AR gene analyzed by capillary electrophoresis. Mean CAG length did not differ significantly between males with azoospermia (22.0 ± 3.1), mild oligozoospermia (22.4 ± 2.6), severe oligozoospermia (23.0 ± 4.2), normozoospermia (21.8 ± 2.4), or known causes of infertility (22.1 ± 2.9) and fertile controls (22.3 ± 2.9). However, we found a significantly higher percentage of CAG repeats >26 (p = 0.022), >27 (p = 0.018) and >28 (p = 0.009) in males with mild oligozoospermia. These results indicate a possible association between CAG repeat length and mild oligozoospermia. Further studies on a larger number of patients with mild oligozoospermia are warranted to confirm this association.

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PALMBERG, C., P. KOIVISTO, L. KAKKOLA, T. L. J. TAMMELA, O. P. KALLIONIEMI, and T. VISAKORPI. "ANDROGEN RECEPTOR GENE AMPLIFICATION AT PRIMARY PROGRESSION PREDICTS RESPONSE TO COMBINED ANDROGEN BLOCKADE AS SECOND LINE THERAPY FOR ADVANCED PROSTATE CANCER." Journal of Urology 164, no. 6 (2000): 1992–95. http://dx.doi.org/10.1016/s0022-5347(05)66935-2.

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Kim, J., L. Jia, M. R. Stallcup, and G. A. Coetzee. "The role of protein kinase A pathway and cAMP responsive element-binding protein in androgen receptor-mediated transcription at the prostate-specific antigen locus." Journal of Molecular Endocrinology 34, no. 1 (2005): 107–18. http://dx.doi.org/10.1677/jme.1.01701.

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Androgen-independent prostate cancer is a lethal form of the disease that is marked by metastasis and rapid proliferation in its final stages. As no effective therapy for this aggressive tumor currently exists, it is imperative to elucidate and target the mechanisms involved in the progression to androgen independence. Accumulating evidence indicates that aberrant activation of androgen receptor (AR) via signal transduction pathways, AR gene mutation and/or amplification, and/or coregulator alterations may contribute to the progression of prostate cancer. In the present study, the effects of protein kinase A (PKA) signaling and its downstream factors on AR activity at the prostate-specific antigen (PSA) gene were tested. Activation of PKA by forskolin resulted in enhanced androgen-induced expression of the PSA gene, an effect that was blocked by the AR antagonist, bicalutamide. Interestingly, when either p300 or CBP was overexpressed, PKA activation was sufficient to stimulate PSA promoter-driven transcription in the absence of androgen, which was not inhibited by bicalutamide. PKA activation did not significantly alter AR protein levels but significantly increased the phosphorylated form of its downstream effector, cAMP responsive element-binding protein (CREB) in the presence of androgen. Furthermore, chromatin immunoprecipitation showed that the combination of androgen and forskolin increased phosphorylated CREB occupancy, which was accompanied by histone acetylation, at the putative cAMP responsive element located in the 5′ upstream regulatory region of the PSA gene. Remarkably, mammalian two-hybrid assay indicated that p300/CBP may bridge the interaction between AR and CREB, suggesting a novel enhanceosomal cooperation. These results demonstrate an intriguing interplay between a signal transduction pathway, coactivator overexpression and AR signaling as a possible combined mechanism of progression to androgen-independent prostate cancer.

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Foley, Ruth, Donal Hollywood, and Mark Lawler. "Molecular pathology of prostate cancer: the key to identifying new biomarkers of disease." Endocrine-Related Cancer 11, no. 3 (2004): 477–88. http://dx.doi.org/10.1677/erc.1.00699.

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Microarray technology has recently accelerated the study of the molecular events involved in prostate cancer, offering the prospect of more precise prognosis and new therapeutic strategies. This review summarises current knowledge of the molecular pathology of prostate cancer. The expression and function of numerous genes have been shown to be altered in prostate cancer. Many of these genes are involved in cell cycle regulation, steroid hormone metabolism or regulation of gene expression. The mechanisms by which androgen independence arises are discussed, including cross-activation, gene amplification and point mutations of the androgen receptor. Analysis of changes in the levels of expression of large numbers of genes during prostate cancer progression have provided a better understanding of the basis of the disease, yielding new molecular markers, such as hepsin, with potential use in diagnosis and prognosis.

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Koivisto, Pasi, Tapio Visakorpi, and Olli-P. Kallioniemi. "Androgen receptor gene amplification: A novel molecular mechanism for endocrine therapy resistance in human prostate cancer." Scandinavian Journal of Clinical and Laboratory Investigation 56 (1996): 57–63. http://dx.doi.org/10.3109/00365519609168299.

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Makkonen, Harri, Miia Kauhanen, Tiina Jääskeläinen, and Jorma J. Palvimo. "Androgen receptor amplification is reflected in the transcriptional responses of Vertebral-Cancer of the Prostate cells." Molecular and Cellular Endocrinology 331, no. 1 (2011): 57–65. http://dx.doi.org/10.1016/j.mce.2010.08.008.

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Multer, George L., and Kevin A. Boynton. "PCR bias in amplification of androgen receptor alleles, a trinucleotide repeat marker used in clonality studies." Nucleic Acids Research 23, no. 8 (1995): 1411–18. http://dx.doi.org/10.1093/nar/23.8.1411.

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Koivisto, Pasi, Tapio Visakorpi, and Olli-P. Kallioniemi. "Androgen receptor gene amplification: A novel molecular mechanism for endocrine therapy resistance in human prostate cancer." Scandinavian Journal of Clinical and Laboratory Investigation 56, sup226 (1996): 57–63. http://dx.doi.org/10.1080/00365519609168299.

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Porter, Laura H., Andrew Bakshi, David Pook, et al. "Androgen receptor enhancer amplification in matched patient‐derived xenografts of primary and castrate‐resistant prostate cancer." Journal of Pathology 254, no. 2 (2021): 121–34. http://dx.doi.org/10.1002/path.5652.

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Zellweger, Tobias, Susanne Stürm, Silvia Rey та ін. "Estrogen receptor β expression and androgen receptor phosphorylation correlate with a poor clinical outcome in hormone-naïve prostate cancer and are elevated in castration-resistant disease". Endocrine-Related Cancer 20, № 3 (2013): 403–13. http://dx.doi.org/10.1530/erc-12-0402.

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Patients with advanced prostate cancer (PC) are usually treated with androgen withdrawal. While this therapy is initially effective, nearly all PCs become refractory to it. As hormone receptors play a crucial role in this process, we constructed a tissue microarray consisting of PC samples from 107 hormone-naïve (HN) and 101 castration-resistant (CR) PC patients and analyzed the androgen receptor (AR) gene copy number and the protein expression profiles of AR, Serin210-phosphorylated AR (pAR210), estrogen receptor (ER)β, ERα and the proliferation marker Ki67. The amplification of the AR gene was virtually restricted to CR PC and was significantly associated with increased AR protein expression (P<0.0001) and higher tumor cell proliferation (P=0.001). Strong AR expression was observed in a subgroup of HN PC patients with an adverse prognosis. In contrast, the absence of AR expression in CR PC was significantly associated with a poor overall survival. While pAR210 was predominantly found in CR PC patients (P<0.0001), pAR210 positivity was observed in a subgroup of HN PC patients with a poor survival (P<0.05). Epithelial ERα expression was restricted to CR PC cells (9%). ERβ protein expression was found in 38% of both HN and CR PCs, but was elevated in matched CR PC specimens. Similar to pAR210, the presence of ERβ in HN patients was significantly associated with an adverse prognosis (P<0.005). Our results strongly suggest a major role for pAR210 and ERβ in HN PC. The expression of these markers might be directly involved in CR tumor growth.

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Faber, P. W., A. King, H. C. J. van Rooij, A. O. Brinkmann, N. J. de Both, and J. Trapman. "The mouse androgen receptor. Functional analysis of the protein and characterization of the gene." Biochemical Journal 278, no. 1 (1991): 269–78. http://dx.doi.org/10.1042/bj2780269.

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Screening a mouse genomic DNA library with human androgen-receptor (hAR) cDNA probes resulted in the isolation and characterization of eight genomic fragments that contain the eight exons of the mouse androgen-receptor (mAR) gene. On the basis of similarity to the hAR gene, the nucleotide sequences of the protein-coding parts of the exons as well as the sequences of the intron/exon boundaries were determined. An open reading frame (ORF) of 2697 nucleotides, which can encode an 899-amino-acid protein, could be predicted. The structure of the mAR ORF was confirmed by sequence analysis of mAR cDNA fragments, which were obtained by PCR amplification of mouse testis cDNA, using mAR specific primers. A eukaryotic mAR expression vector was constructed and mAR was transiently expressed in COS-1 cells. The expressed protein was shown by Western blotting to be identical in size with the native mAR. Co-transfection of HeLa cells with the mAR expression plasmid and an androgen-responsive chloramphenicol acetyltransferase (CAT) reporter-gene construct showed mAR to be able to trans-activate the androgen-responsive promoter in a ligand-dependent manner. Transcription-initiation sites of the mAR gene were identified by S1-nuclease protection experiments, and the functional activity of the promoter region was determined by transient expression of mAR promoter-CAT-reporter-gene constructs in HeLa cells. Structural analysis revealed the promoter of the mAR gene to be devoid of TATA/CCAAT elements. In addition, the promoter region is not remarkably (G + C)-rich. Potential promoter elements consist of a consensus Sp1 binding sequence and a homopurine stretch. The polyadenylation sites of mAR mRNA were identified by sequence similarity to the corresponding sites in the hAR mRNA.

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Bose, Rohit, Wassim Abida, Phillip Iaquinta, et al. "Investigation of a frequently mutated transcriptional repressor in prostate cancer, in particular its role in modulating androgen signaling and its effects on TMPRSS2-ERG dependent tumor maintenance." Journal of Clinical Oncology 34, no. 2_suppl (2016): 274. http://dx.doi.org/10.1200/jco.2016.34.2_suppl.274.

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274 Background: Recent genomic profiling of primary and metastatic prostate cancers revealed up to 27% of tumors contain putative loss-of-function point mutations or copy number deletions within the gene ERF, an ETS transcriptional repressor with a remarkably similar DNA-binding domain to the TMPRSS2-ERG gene product. Methods: Bioinformatic analysis of 450 patient tumors was obtained from the TCGA and SU2C datasets. Transcriptomic and cistromic analysis was achieved by RNA-seq and ChIP-seq on VCaP cells, as well as patient-derived organoid cultures of both normal and neoplastic prostates. Gene expression was inhibited by CRISPR or shRNA technology. Results: ERF copy number deletions are associated with Gleason 8+ primary disease (p = 0.0369), and ERF mRNA level inversely correlates with androgen-driven transcription (p < 0.0001) in the absence of androgen receptor amplification. Transient inhibition of ERG expression in TMPRSS2-ERG+ cancer models leads to a contraction of the androgen transcriptome. On the other hand, inhibition of ERF leads to an expansion of the androgen transcriptome, and moreover, supersedes the opposing effects of ERG. ERF and the TMPRSS2-ERG gene product have overlapping ETS cistromes that are associated with androgen-receptor binding sites; inhibition of one leads to occupancy at the vacated sites by the other. CRISPR-mediated inhibition of ERG in TMPRSS2-ERG+ models leads to a complete halt of growth, but concomitant loss of ERF partially restores cellular proliferation. Conclusions: ERF is a tumor suppressor with genomic loss-of-function mutations in up to 27% of prostate cancers, thereby expanding the concept of an ETS positive subtype. ERF occupies ETS sites of androgen-regulated genes and is an endogenous dampener of their transcription. Moreover, even in tumors lacking ERF mutations, upregulated ERG now occupies many of these same ETS sites, unmasking their transcriptional control by androgen. Thus, a key oncogenic activity of TMPRSS2-ERG is to antagonize endogenous ERF.

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Sammarco, Innocenzo, Paola Grimaldi, Pellegrino Rossi, et al. "Novel Point Mutation in the Splice Donor Site of Exon-Intron Junction 6 of the Androgen Receptor Gene in a Patient with Partial Androgen Insensitivity Syndrome*." Journal of Clinical Endocrinology & Metabolism 85, no. 9 (2000): 3256–61. http://dx.doi.org/10.1210/jcem.85.9.6815.

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Abstract Androgen receptor (AR) gene mutations have been shown to cause androgen insensitivity syndrome with altered sexual differentiation in XY individuals, ranging from a partial insensitivity with male phenotype and azoospermia to a complete insensitivity with female phenotype and the absence of pubic and axillary sexual hair after puberty. In this study we present an 11-yr-old XY girl, with clinical manifestations peculiar for impaired androgen biological action, including female phenotype, blind-ending vagina, small degree of posterior labial fusion, and absence of uterus, fallopian tubes, and ovaries. At the time of the diagnosis the patient had a FSH/LH ratio according to the puberal stage, undetectable 17β-estradiol, and high levels of testosterone (80.1 ng/mL). After bilateral gonadectomy, performed at the age of 11 yr, histological examination showed small embryonic seminiferous tubules containing prevalently Sertoli cells and occasional spermatogonia together with abundant fibrous tissue. Molecular study of the patient showed a guanine to thymine transversion in position +5 of the donor splice site in the junction between exon 6 and intron 6 of the AR gene. The result of RT-PCR amplification of the AR messenger ribonucleic acid from cultured genital skin fibroblasts of the patient suggests that splicing is defective, and intron 6 is retained in most of the receptor messenger ribonucleic acid molecules. We show by immunoblotting that most of the expressed protein lacks part of the C-terminal hormone-binding domain, and a small amount of normal receptor is observed. This is probably responsible for the reduced binding capacity in genital skin fibroblasts of the patient. The molecular basis of the alteration in this case is a novel, uncommon mutation, leading to a phenotype indicative of a partial androgen insensitivity syndrome, Quigley’s grade 5.

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Shiota, Masaki, Yohei Sekino, Shigehiro Tsukahara, et al. "Gene amplification of YB‐1 in castration‐resistant prostate cancer in association with aberrant androgen receptor expression." Cancer Science 112, no. 1 (2020): 323–30. http://dx.doi.org/10.1111/cas.14695.

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ZHANG, XIAN, SHI-ZHE HONG, ER-JIANG LIN, DA-YA WANG, ZHI-JIA LI, and LI CHEN. "Amplification and protein expression of androgen receptor gene in prostate cancer cells: Fluorescence in situ hybridization analysis." Oncology Letters 9, no. 6 (2015): 2617–22. http://dx.doi.org/10.3892/ol.2015.3114.

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