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Cells Dec 2020Around 80-90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum... (Review)
Review
Around 80-90% of prostate cancer (PCa) cases are dependent on androgens at initial diagnosis; hence, androgen ablation therapy directed toward a reduction in serum androgens and the inhibition of androgen receptor (AR) is generally the first therapy adopted. However, the patient's response to androgen ablation therapy is variable, and 20-30% of PCa cases become castration resistant (CRPCa). Several mechanisms can guide treatment resistance to anti-AR molecules. In this regard, AR-dependent and -independent resistance mechanisms can be distinguished within the AR pathway. In this article, we investigate the multitude of AR signaling aspects, encompassing the biological structure of AR, current AR-targeted therapies, mechanisms driving resistance to AR, and AR crosstalk with other pathways, in an attempt to provide a comprehensive review for the PCa research community. We also summarize the new anti-AR drugs approved in non-metastatic castration-resistant PCa, in the castration-sensitive setting, and combination therapies with other drugs.
Topics: Androgen Receptor Antagonists; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms; Receptors, Androgen; Signal Transduction
PubMed: 33321757
DOI: 10.3390/cells9122653 -
Molecules (Basel, Switzerland) Jan 2020The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy among females worldwide. The... (Review)
Review
The Androgen Receptor (AR) is emerging as an important factor in the pathogenesis of breast cancer (BC), which is the most common malignancy among females worldwide. The concordance of more than 70% of AR expression in primary and metastatic breast tumors implies that AR may be a new marker and a potential therapeutic target among AR-positive breast cancer patients. Biological insight into AR-positive breast cancer reveals that AR may cross-talk with several vital signaling pathways, including key molecules and receptors. AR exhibits different behavior depending on the breast cancer subtype. Preliminary clinical research using AR-targeted drugs, which have already been FDA-approved for prostate cancer (PC), has given promising results for AR-positive breast cancer patients. However, since the prognostic and predictive value of AR positivity remains uncertain, it is difficult to identify and stratify patients that would benefit from AR-targeted therapies. Herein, through a review of preclinical studies, clinical studies, and clinical trials, we summarize the biology of AR, its prognostic and predictive value, as well as its therapeutic implications by breast cancer molecular subtype.
Topics: Animals; Antineoplastic Agents; Breast Neoplasms; Drug Evaluation, Preclinical; Female; Humans; Molecular Targeted Therapy; Receptors, Androgen; Signal Transduction
PubMed: 31952272
DOI: 10.3390/molecules25020358 -
Acta Pharmacologica Sinica Jan 2015Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and... (Review)
Review
Androgens and androgen receptors (AR) play a pivotal role in expression of the male phenotype. Several diseases, such as androgen insensitivity syndrome (AIS) and prostate cancer, are associated with alterations in AR functions. Indeed, androgen blockade by drugs that prevent the production of androgens and/or block the action of the AR inhibits prostate cancer growth. However, resistance to these drugs often occurs after 2-3 years as the patients develop castration-resistant prostate cancer (CRPC). In CRPC, a functional AR remains a key regulator. Early studies focused on the functional domains of the AR and its crucial role in the pathology. The elucidation of the structures of the AR DNA binding domain (DBD) and ligand binding domain (LBD) provides a new framework for understanding the functions of this receptor and leads to the development of rational drug design for the treatment of prostate cancer. An overview of androgen receptor structure and activity, its actions in prostate cancer, and how structural information and high-throughput screening have been or can be used for drug discovery are provided herein.
Topics: Androgens; Animals; Drug Discovery; Humans; Male; Prostatic Neoplasms; Receptors, Androgen
PubMed: 24909511
DOI: 10.1038/aps.2014.18 -
Androgen receptor-mediated CD8 T cell stemness programs drive sex differences in antitumor immunity.Immunity Jul 2022The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying...
The incidence and mortality rates of many non-reproductive human cancers are generally higher in males than in females. However, the immunological mechanism underlying sexual differences in cancers remains elusive. Here, we demonstrated that sex-related differences in tumor burden depended on adaptive immunity. Male CD8 T cells exhibited impaired effector and stem cell-like properties compared with female CD8 T cells. Mechanistically, androgen receptor inhibited the activity and stemness of male tumor-infiltrating CD8 T cells by regulating epigenetic and transcriptional differentiation programs. Castration combined with anti-PD-L1 treatment synergistically restricted tumor growth in male mice. In humans, fewer male CD8 T cells maintained a stem cell-like memory state compared with female counterparts. Moreover, AR expression correlated with tumor-infiltrating CD8 T cell exhaustion in cancer patients. Our findings reveal sex-biased CD8 T cell stemness programs in cancer progression and in the responses to cancer immunotherapy, providing insights into the development of sex-based immunotherapeutic strategies for cancer treatment.
Topics: Animals; CD8-Positive T-Lymphocytes; Female; Humans; Immunotherapy; Male; Mice; Neoplasms; Receptors, Androgen; Sex Characteristics; Tumor Microenvironment
PubMed: 35700739
DOI: 10.1016/j.immuni.2022.05.012 -
Molecular and Cellular Endocrinology Apr 2018The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which... (Review)
Review
The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.
Topics: Androgens; Animals; Humans; Models, Biological; Organ Specificity; Receptors, Androgen
PubMed: 28624515
DOI: 10.1016/j.mce.2017.06.013 -
International Journal of Impotence... Dec 2022Selective androgen receptor modulators (SARMs) are a class of androgen receptor ligands that bind androgen receptors and display tissue selective activation of...
Selective androgen receptor modulators (SARMs) are a class of androgen receptor ligands that bind androgen receptors and display tissue selective activation of androgenic signaling. SARMs have selective anabolic effects on muscle and bone, and were originally synthesized for treatment of muscle wasting conditions, osteoporosis, breast cancer. To date, no SARM has been clinically approved and little is known about the beneficial effects and other adverse effects on users. We examined the adverse effects and potential benefits of SARMs amongst users. We performed an internet survey assessing the demographics of users via a 32-question survey. Using reddit as a platform, we distributed the survey through various subreddits that included potential SARMs users. Out of the 520 responses, 343 participants admitted having used SARMs. Most were males (98.5%), between the ages of 18-29 (72.3%). More than 90% of users acquired SARMs via the internet and did not consult with a physician. More than half of SARMs users experienced side effects including mood swings, decreased testicular size, and acne. More than 90% of men reported increased muscle mass and were satisfied with their SARMs usage. Despite having seemingly positive effects, more than 50% of SARMs users report significant adverse effects. Chi square was the main method of statistical analysis. Future studies should focus on comprehensive reproductive evaluation of men using SARMs.
Topics: Adolescent; Adult; Female; Humans; Male; Young Adult; Androgens; Cross-Sectional Studies; Receptors, Androgen; Signal Transduction
PubMed: 34471228
DOI: 10.1038/s41443-021-00465-0 -
Steroids Dec 2020Anabolic androgenic steroids (AAS) are testosterone and testosterone-derivative compounds sporadically employed by athletes and increasingly used recreationally to... (Review)
Review
Considerations, possible contraindications, and potential mechanisms for deleterious effect in recreational and athletic use of selective androgen receptor modulators (SARMs) in lieu of anabolic androgenic steroids: A narrative review.
Anabolic androgenic steroids (AAS) are testosterone and testosterone-derivative compounds sporadically employed by athletes and increasingly used recreationally to acquire a competitive edge or improve body composition. Nevertheless, users are subject to undesired side effects majorly associated with tissue-specific androgen receptor (AR) binding-mediated actions. More recently, selective AR modulators (SARMs) have gained popularity towards delivering androgen-associated anabolic actions with hopes of minimal androgenic effects. While several SARMs are in preclinical and clinical phases intended for demographics subject to hypogonadism, muscle wasting, and osteoporosis, several athletic organizations and drug testing affiliates have realized the increasingly widespread use of SARMs amongst competitors and have subsequently banned their use. Furthermore, recreational users are haphazardly acquiring these compounds from the internet and consuming doses several times greater than empirically reported. Unfortunately, online sources are rife with potential contamination, despite a prevailing public opinion suggesting SARMs are innocuous AAS alternatives. Considering each agent has a broad range of supporting evidence in both human and non-human models, it is important to comprehensively evaluate the current literature on commercially available SARMs to gain better understanding of their efficacy and if they can truly be considered a safer AAS alternative. Therefore, the purpose of this review is to discuss the current evidence regarding AAS and SARM mechanisms of action, demonstrate the efficacy of several prominent SARMs in a variety of scientific trials, and theorize on the wide-ranging contraindications and potential deleterious effects, as well as potential future directions regarding acute and chronic SARM use across a broad range of demographics.
Topics: Anabolic Agents; Androgen Antagonists; Animals; Humans; Male; Receptors, Androgen
PubMed: 33148520
DOI: 10.1016/j.steroids.2020.108753 -
International Journal of Biological... 2023Androgenetic alopecia (AGA) affects more than half of the adult population worldwide and is primarily caused by the binding of dihydrotestosterone (DHT) to androgen...
Androgenetic alopecia (AGA) affects more than half of the adult population worldwide and is primarily caused by the binding of dihydrotestosterone (DHT) to androgen receptors (AR). However, the mechanisms by which AR affects hair follicles remain unclear. In our study, we found that miR-221 significantly suppressed hair growth and the proliferation of dermal papilla cells (DPCs) and dermal sheath cells (DSCs) in AGA patients. Interestingly, miR-221 and AR were mainly co-located in the same part of the hair follicle. Mechanistic analysis revealed that AR directly promoted the transcription of miR-221, which in turn suppressed IGF-1 expression, leading to the inactivation of the MAPK pathway in DPCs and the PI3K/AKT pathway in DSCs. In AGA patients, miR-221 expression was positively correlated with AR expression and negatively correlated with IGF-1 expression. Our findings indicate that miR-221, as a direct target of AR, plays a crucial role in the pathogenesis of AGA, making it a novel biomarker and potential therapeutic target for treating AGA.
Topics: Adult; Humans; Alopecia; Insulin-Like Growth Factor I; MicroRNAs; Phosphatidylinositol 3-Kinases; Receptors, Androgen
PubMed: 37496996
DOI: 10.7150/ijbs.80481 -
Small Methods Jan 2023Androgenetic alopecia (AGA) is a transracial and cross-gender disease worldwide with a youth-oriented tendency, but it lacks effective treatment. The binding of androgen...
Androgenetic alopecia (AGA) is a transracial and cross-gender disease worldwide with a youth-oriented tendency, but it lacks effective treatment. The binding of androgen receptor (AR) and androgen plays an essential role in the occurrence and progression of AGA. Herein, novel proteolysis targeting chimera degrader of AR (AR-PROTAC) is synthesized and integrated with dissolving microneedles (PROTAC-MNs) to achieve AR destruction in hair follicles for AGA treatment. The PROTAC-MNs possess adequate mechanical capabilities for precise AR-PROTAC delivery into the hair follicle-residing regions for AR degradation. After applying only once topically, the PROTAC-MNs achieve an accelerated onset of hair regeneration as compared to the daily application of the first-line topical drug minoxidil. Intriguingly, PROTAC-MNs via single administration still realize superior hair regeneration in AGA recrudescence, which is the major drawback of minoxidil in clinical practice. With the degradation of AR, the PROTAC-MNs successfully regulate the signaling cascade related to hair growth and activate hair follicle stem cells. Furthermore, the PROTAC-MNs do not cause systemic toxicity or androgen deficiency-related chaos in vivo. Collectively, these AR-degrading dissolving microneedles with long-lasting efficacy, one-step administration, and high biocompatibility provide a great therapeutic potential for AGA treatment.
Topics: Adolescent; Humans; Administration, Topical; Alopecia; Androgens; Minoxidil; Receptors, Androgen; Proteolysis Targeting Chimera
PubMed: 36538748
DOI: 10.1002/smtd.202201293 -
Molecular Cell Sep 2020Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the...
Steroid receptors activate gene transcription by recruiting coactivators to initiate transcription of their target genes. For most nuclear receptors, the ligand-dependent activation function domain-2 (AF-2) is a primary contributor to the nuclear receptor (NR) transcriptional activity. In contrast to other steroid receptors, such as ERα, the activation function of androgen receptor (AR) is largely dependent on its ligand-independent AF-1 located in its N-terminal domain (NTD). It remains unclear why AR utilizes a different AF domain from other receptors despite that NRs share similar domain organizations. Here, we present cryoelectron microscopy (cryo-EM) structures of DNA-bound full-length AR and its complex structure with key coactivators, SRC-3 and p300. AR dimerization follows a unique head-to-head and tail-to-tail manner. Unlike ERα, AR directly contacts a single SRC-3 and p300. The AR NTD is the primary site for coactivator recruitment. The structures provide a basis for understanding assembly of the AR:coactivator complex and its domain contributions for coactivator assembly and transcriptional regulation.
Topics: Cryoelectron Microscopy; DNA; E1A-Associated p300 Protein; HEK293 Cells; Humans; Nuclear Receptor Coactivator 3; Nucleic Acid Conformation; Protein Conformation; Receptors, Androgen; Recombinant Proteins
PubMed: 32668201
DOI: 10.1016/j.molcel.2020.06.031