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Cancer Letters Nov 2015Cancers arising in the male breast are uncommon. Male breast cancer is a hormone-driven disease that often expresses the estrogen receptor, and antiestrogen therapy... (Review)
Review
Cancers arising in the male breast are uncommon. Male breast cancer is a hormone-driven disease that often expresses the estrogen receptor, and antiestrogen therapy represents the mainstay of treatment. Paradoxically, the advent of a wave of antiestrogens eclipsed the therapeutic potential of alternative therapeutic options. At the beginning of the hormonal therapy era the administration of antiandrogens to metastatic male breast cancer patients was proposed. Ever since the use of these compounds has largely been neglected. A therapeutic role for antiandrogens has been envisioned again in recent years. First, molecular characterization efforts pointed to the androgen receptor as a potential therapeutic target. Second, the development of aromatase inhibitors unexpectedly raised the need for neutralizing androgens in order to tackle endocrine feedback mechanisms responsible for acquired resistance. We herein provide an overview of molecular studies where the androgen receptor was investigated at the genomic, transcriptomic or phenotypic level. We then discuss androgens in the context of the endocrine networks nourishing male breast cancer. Finally, clinical evidence on antiandrogens is summarized along with strategies should be implemented to improve the medical management of these patients.
Topics: Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Breast Neoplasms, Male; Humans; Male; Molecular Targeted Therapy; Neoplasms, Hormone-Dependent; Receptors, Androgen; Signal Transduction; Treatment Outcome
PubMed: 26276719
DOI: 10.1016/j.canlet.2015.07.040 -
Biomolecules Mar 2021The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward... (Review)
Review
The androgen receptor (AR) is one of the main components in the development and progression of prostate cancer (PCa), and treatment strategies are mostly directed toward manipulation of the AR pathway. In the metastatic setting, androgen deprivation therapy (ADT) is the foundation of treatment in patients with hormone-sensitive prostate cancer (HSPC). However, treatment response is short-lived, and the majority of patients ultimately progress to castration-resistant prostate cancer (CRPC). Surmountable data from clinical trials have shown that the maintenance of AR signaling in the castration environment is accountable for disease progression. Study results indicate multiple factors and survival pathways involved in PCa. Based on these findings, the alternative molecular pathways involved in PCa progression can be manipulated to improve current regimens and develop novel treatment modalities in the management of CRPC. In this review, the interaction between AR signaling and other molecular pathways involved in tumor pathogenesis and its clinical implications in metastasis and advanced disease will be discussed, along with a thorough overview of current and ongoing novel treatments for AR signaling inhibition.
Topics: Androgen Receptor Antagonists; Benzamides; Humans; Male; Neoplasm Metastasis; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction; Survival Analysis; Tumor Microenvironment
PubMed: 33805919
DOI: 10.3390/biom11040492 -
Endocrine-related Cancer Aug 2014The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is... (Review)
Review
The androgen receptor (AR) is a ligand-regulated transcription factor that belongs to the family of nuclear receptors. In addition to regulation by steroid, the AR is also regulated by post-translational modifications generated by signal transduction pathways. Thus, the AR functions not only as a transcription factor but also as a node that integrates multiple extracellular signals. The AR plays an important role in many diseases, including complete androgen insensitivity syndrome, spinal bulbar muscular atrophy, prostate and breast cancer, etc. In the case of prostate cancer, dependence on AR signaling has been exploited for therapeutic intervention for decades. However, the effectiveness of these therapies is limited in advanced disease due to restoration of AR signaling. Greater understanding of the molecular mechanisms involved in AR action will enable the development of improved therapeutics to treat the wide range of AR-dependent diseases. The AR is subject to regulation by a number of kinases through post-translational modifications on serine, threonine, and tyrosine residues. In this paper, we review the AR phosphorylation sites, the kinases responsible for these phosphorylations, as well as the biological context and the functional consequences of these phosphorylations. Finally, what is known about the state of AR phosphorylation in clinical samples is discussed.
Topics: Animals; Humans; Phosphorylation; Protein Kinases; Protein Structure, Tertiary; Receptors, Androgen
PubMed: 24424504
DOI: 10.1530/ERC-13-0472 -
European Review For Medical and... Feb 2021Triple-negative breast cancers (TNBC) include a heterogeneous group of diseases, characterized by the lack of estrogen receptor (ER), progesterone receptor (PgR), and...
OBJECTIVE
Triple-negative breast cancers (TNBC) include a heterogeneous group of diseases, characterized by the lack of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) expression. TNBC that shows an overexpression of the androgen receptor (AR) defines the phenotype known as "luminal androgen receptor" (LAR), while the absence of the AR defines a "quadruple negative breast cancer" (QNBC). Several reports have associated AR positivity with a lower response to neoadjuvant chemotherapy (NAC), while divergent data have been reported about the impact of AR positivity on survival. The aim of this study was to retrospectively review our series of patients with TNBC tested for AR and submitted to NAC and compare pathologic complete response (pCR) rates in patients with a LAR phenotype or with QNBC.
PATIENTS AND METHODS
The clinical records of all patients with TNBC tested for AR that underwent NAC at our Institution from January 1, 2015 to June 30, 2019 were reviewed. Histopathological features as well as ER, PgR, Ki67, HER2 values, clinical and pathological stage, and results of BRCA gene expression profiling were registered for all patients.
RESULTS
Of the 145 TNBC patients treated by NAC, 20 (13.8%) had a LAR phenotype, while 125 (86.2%) had a QNBC. Overall, a pCR was achieved in 52 patients (35.8%). Patients with LAR phenotype had a lower rate of pCR as compared to patients with QNBC phenotype (25% vs. 37.6%). High Ki67 values (>50%) were observed less frequently in patients with a LAR phenotype (50% vs. 76.8% in QNBC).
CONCLUSIONS
Our data seem to confirm that the LAR phenotype is associated to lower rates of pCR after neoadjuvant chemotherapy; routine assessment of AR expression in addition to classical biomarkers in patients with TNBC could help to better personalize treatment.
Topics: Female; Humans; Middle Aged; Neoadjuvant Therapy; Receptors, Androgen; Triple Negative Breast Neoplasms
PubMed: 33660830
DOI: 10.26355/eurrev_202102_25087 -
Frontiers in Endocrinology 2022Androgen receptor signaling pathway is necessary to complete spermatogenesis in testes. Difference between androgen binding location in Sertoli cell classifies androgen... (Review)
Review
Androgen receptor signaling pathway is necessary to complete spermatogenesis in testes. Difference between androgen binding location in Sertoli cell classifies androgen receptor signaling pathway into classical signaling pathway and non-classical signaling pathway. As the only somatic cell type in seminiferous tubule, Sertoli cells are under androgen receptor signaling pathway regulation androgen receptor located in cytoplasm and plasma membrane. Androgen receptor signaling pathway is able to regulate biological processes in Sertoli cells as well as germ cells surrounded between Sertoli cells. Our review will summarize the major discoveries of androgen receptor signaling pathway in Sertoli cells and the paracrine action on germ cells. Androgen receptor signaling pathway regulates Sertoli cell proliferation and maturation, as well as maintain the integrity of blood-testis barrier formed between Sertoli cells. Also, Spermatogonia stem cells achieve a balance between self-renewal and differentiation under androgen receptor signaling regulation. Meiotic and post-meiotic processes including Sertoli cell - Spermatid attachment and Spermatid development are guaranteed by androgen receptor signaling until the final sperm release. This review also includes one disease related to androgen receptor signaling dysfunction named as androgen insensitivity syndrome. As a step further ahead, this review may be conducive to develop therapies which can cure impaired androgen receptor signaling in Sertoli cells.
Topics: Humans; Male; Receptors, Androgen; Sertoli Cells; Signal Transduction; Spermatogenesis; Testis
PubMed: 35282467
DOI: 10.3389/fendo.2022.838858 -
Drug Resistance Updates : Reviews and... May 2021The treatment landscape of advanced prostate cancer has widely expanded over the past years with androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy... (Review)
Review
The treatment landscape of advanced prostate cancer has widely expanded over the past years with androgen receptor signaling inhibitors (ARSIs) and taxane chemotherapy moving to earlier disease stages in the treatment of prostate cancer. With the increasing use of ARSIs in earlier disease stages, cross-resistance between treatments has emerged, which is a dominant impediment in current clinical practice. To overcome cross-resistance in the treatment of prostate cancer, it is of paramount importance to decipher the mechanisms of cross-resistance between ARSIs and between ARSIs and chemotherapy. Here, molecular mechanisms of resistance to the available therapies including androgen receptor (AR) splice variants, AR overexpression, AR mutations and glucocorticoid receptor upregulation are described. Based on these underlying mechanisms, clinical data of cross-resistance between ARSIs and chemotherapy have been reported. Only recently these data have been confirmed in prospective randomized trials. From these studies, it has become clear that sequential ARSI treatment has no place in the treatment of advanced prostate cancer due to emerging drug resistance. In addition, based on prospective evidence, we argue that it is worth considering an early switch to cabazitaxel treatment in case of lack of benefit on docetaxel regimen after an ARSI treatment. Based on these new insights from randomized trials, several recommendations for treatment sequence are proposed.
Topics: Antineoplastic Agents; Drug Interactions; Drug Resistance, Neoplasm; Humans; Male; Neoplasm Staging; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction
PubMed: 33799049
DOI: 10.1016/j.drup.2021.100761 -
Endocrine-related Cancer Aug 2014As prostate cancer (PCa) progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the... (Review)
Review
As prostate cancer (PCa) progresses to the lethal castration resistant and metastatic form, genetic and epigenetic adaptation, clonal selection, and evolution of the tumor microenvironment contribute to the emergence of unique biological characteristics under the selective pressure of external stresses. These stresses include the therapies applied in the clinic or laboratory and the exposures of cancers to hormonal, paracrine, or autocrine stimuli in the context of the tumor micro- and macro-environment. The androgen receptor (AR) is a key gene involved in PCa etiology and oncogenesis, including disease development, progression, response to initial hormonal therapies, and subsequent resistance to hormonal therapies. Alterations in the AR signaling pathway have been observed in certain selection contexts and contribute to the resistance to agents that target hormonal regulation of the AR, including standard androgen deprivation therapy, antiandrogens such as enzalutamide, and androgen synthesis inhibition with abiraterone acetate. One such resistance mechanism is the synthesis of constitutively active AR variants lacking the canonical ligand-binding domain. This review focuses on the etiology, characterization, biological properties, and emerging data contributing to the clinical characteristics of AR variants, and suggests approaches to full-length AR and AR variant biomarker validation, assessment, and systemic targeting in the clinic.
Topics: Animals; Biomarkers, Tumor; Disease Progression; Genetic Variation; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen
PubMed: 24859991
DOI: 10.1530/ERC-13-0470 -
Nucleic Acids Research Jan 2023Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust...
Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by specific genomic regions known as super-enhancers (SEs). The robust transcription of genes at such SEs is enabled by the formation of phase-separated condensates by transcription factors and coactivators with intrinsically disordered regions. The androgen receptor (AR), the main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the transcriptional coactivator mediator complex subunit 1 (MED1) to SEs in androgen-dependent PCa cells, thereby promoting oncogenic transcriptional programs. In this work, we reveal that full-length AR forms foci with liquid-like properties in different PCa models. We demonstrate that foci formation correlates with AR transcriptional activity, as this activity can be modulated by changing cellular foci content chemically or by silencing MED1. AR ability to phase separate was also validated in vitro by using recombinant full-length AR protein. We also demonstrate that AR antagonists, which suppress transcriptional activity by targeting key regions for homotypic or heterotypic interactions of this receptor, hinder foci formation in PCa cells and phase separation in vitro. Our results suggest that enhanced compartmentalization of AR and coactivators may play an important role in the activation of oncogenic transcription programs in androgen-dependent PCa.
Topics: Male; Humans; Receptors, Androgen; Androgens; Transcription Factors; Gene Expression Regulation; Prostatic Neoplasms; Gene Expression; Cell Line, Tumor; Gene Expression Regulation, Neoplastic
PubMed: 36535377
DOI: 10.1093/nar/gkac1158 -
Trends in Endocrinology and Metabolism:... Sep 2022Endometrial cancer (EC) is a gynecological pathology that affects the uterine inner lining. In recent years, genomic studies revealed continually evolving mutational... (Review)
Review
Endometrial cancer (EC) is a gynecological pathology that affects the uterine inner lining. In recent years, genomic studies revealed continually evolving mutational landscapes of endometrial tumors that hold great potential for tailoring therapeutic strategies. This review aims to broaden our knowledge of EC biology by focusing on the role of androgen hormones. First, we discuss epidemiological evidence implicating androgens with EC pathogenesis and cover their biosynthesis and metabolism to bioactive 11-oxyandrogens. Next, we explore the endometrial tumor tissue and the altered microbiota as alternative sources of androgens and their 11-oxymetabolites in EC patients. Finally, we discuss the biological significance of androgens' genomic and nongenomic signaling as part of a medley of pathways ultimately deciding the fate of cells.
Topics: Androgens; Biology; Endometrial Neoplasms; Endometrium; Female; Humans; Receptors, Androgen
PubMed: 35879182
DOI: 10.1016/j.tem.2022.06.001 -
Molecular and Cellular Endocrinology Jan 2012Human androgen receptor (AR) transcriptional activity involves interdomain and coactivator interactions with the agonist-bound AR ligand binding domain (LBD). Structural... (Review)
Review
Human androgen receptor (AR) transcriptional activity involves interdomain and coactivator interactions with the agonist-bound AR ligand binding domain (LBD). Structural determinants of the AR NH(2)- and carboxyl-terminal interaction between the AR NH(2)-terminal FXXLF motif and activation function 2 (AF2) in the LBD were shown previously by crystallography. In this report, we provide evidence for a region in AR LBD helix 12 outside the AF2 binding cleft that facilitates interactions with the FXXLF and LXXLL motifs. Mutagenesis of glutamine 902 to alanine in AR LBD helix 12 (Q902A) disrupted AR FXXLF motif binding to AF2, but enhanced coactivator LXXLL motif binding. Functional compensation for defective FXXLF motif binding by AR-Q902A was suggested by the slower dissociation rate of bound androgen. Functional importance of glutamine 902 was indicated by the charged residue germline mutation Q902R that caused partial androgen insensitivity, and a similar somatic mutation Q902K reported in prostate cancer, both of which increased the androgen dissociation rate and decreased AR transcriptional activity. High affinity equilibrium androgen binding was retained by alanine substitution mutations at Tyr-739 in AR LBD helix 5 or Lys-905 in helix 12 structurally adjacent to AF2, whereas transcriptional activity decreased and the androgen dissociation increased. Deleterious effects of these loss of function mutations were rescued by the helix stabilizing AR prostate cancer somatic mutation H874Y. Sequence NH(2)-terminal to the AR FXXLF motif contributed to the AR NH(2)- and carboxyl-terminal interaction based on greater AR-2-30 FXXLF motif peptide binding to the agonist-bound AR LBD than a shorter AR-20-30 FXXLF motif peptide. We conclude that helix 12 residues outside the AF2 binding cleft modulate AR transcriptional activity by providing flexibility to accommodate FXXLF or LXXLL motif binding.
Topics: Amino Acid Motifs; Amino Acid Substitution; Androgens; Animals; Binding Sites; Crystallography, X-Ray; Dihydrotestosterone; Gene Expression Regulation; Humans; Models, Molecular; Nuclear Receptor Coactivator 2; Protein Structure, Tertiary; Receptors, Androgen; Surface Properties; Transcriptional Activation
PubMed: 21664945
DOI: 10.1016/j.mce.2011.03.026