The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Abstract

Androgen receptor (AR) is the most widely expressed steroid receptor protein in normal breast tissue and is detectable in approximately 90% of primary breast cancers and 75% of metastatic lesions. However, the role of AR in breast cancer development and progression is mired in controversy with evidence suggesting it can either inhibit or promote breast tumorigenesis. Studies have shown it to antagonize estrogen receptor alpha (ERα) DNA binding, thereby preventing pro-proliferative gene transcription; whilst others have demonstrated AR to take on the mantle of a pseudo ERα particularly in the setting of triple negative breast cancer. Evidence for a potentiating role of AR in the development of endocrine resistant breast cancer has also been mounting with reports associating high AR expression with poor response to endocrine treatment. The resurgence of interest into the function of AR in breast cancer has resulted in various emergent clinical trials evaluating anti-AR therapy and selective androgen receptor modulators in the treatment of advanced breast cancer. Trials have reported varied response rates dependent upon subtype with overall clinical benefit rates of ~19–29% for anti-androgen monotherapy, suggesting that with enhanced patient stratification AR could prove efficacious as a breast cancer therapy. Androgens and AR have been reported to facilitate tumor stemness in some cancers; a process which may be mediated through genomic or non-genomic actions of the AR, with the latter mechanism being relatively unexplored in breast cancer. Steroidogenic ligands of the AR are produced in females by the gonads and as sex-steroid precursors secreted from the adrenal glands. These androgens provide an abundant reservoir from which all estrogens are subsequently synthesized and their levels are undiminished in the event of standard hormonal therapeutic intervention in breast cancer. Steroid levels are known to be altered by lifestyle factors such as diet and exercise; understanding their potential role in dictating the function of AR in breast cancer development could therefore have wide-ranging effects in prevention and treatment of this disease. This review will outline the endogenous biochemical drivers of both genomic and non-genomic AR activation and how these may be modulated by current hormonal therapies.

ARe we there yet? Understanding androgen receptor signaling in breast cancer

“…Further, inhibition of AR resulted in decreased levels of phospho-Elk1, phospho-RSK, and c-FOS in xenograft tumors and in patient tumors, corresponding to a decrease in ERK target proteins 46 . In TNBC, AR inhibition has also been shown to modulate the activity of the Ca 2+ -activated K + channel, K Ca 1.1, which is associated with breast cancer invasion and metastasis 47,48 . Multiple groups have also studied the role of cytoplasmic AR phosphorylation 49,50 ; however, additional work is required to understand how AR modifications influence cellular function and localization.…”

“…npj Breast Cancer (2020)47 Published in partnership with the Breast Cancer Research Foundation1234567890():,;…”

Effects of natural polyphenol-rich pomegranate juice on the acute and delayed response of Homocysteine and steroidal hormones following weightlifting exercises: a double-blind, placebo-controlled trial

“…In this context, it was previously shown that antioxidant supplements such as quercetin, vitamin C and/or vitamin E attenuate the increase in mitochondrial biogenesis after endurance training [84,85] and significantly blunt strength gains after 10 weeks of resistance training in recreationally active men [86]. On the other hand, the present reduction in the plasma post-exercise T using POMj could be caused by increased uptake of T (primary androgen receptor (AR)activating hormone [87]) into skeletal muscle during exercise to bind to the androgen receptor and thereby provide an increased anabolic stimulus to promote bone development and protein synthesis within the muscular system [61]. If confirmed, polyphenol-rich nutrients might have the potential to improve acute and chronic adaptations to resistance exercises without limiting muscular training gains.…”

Allosteric Binding Sites On Nuclear Receptors: Focus On Drug Efficacy and Selectivity

“…The higher aromaticity of the AR AF-2 site compared to the ERs likely reflects its preference for phenylalanine or tryptophan residues as opposed to leucines in coactivator fragments [15]. Notably, simultaneous binding to multiple NRs can be desired in certain therapeutic scenarios as for the inhibition of the AR in breast cancer treatment, since it might adopt roles of ERα when the function of this receptor is absent due to pharmacological inhibition [46]. Therefore, compounds binding to both AR and ERα, such as several ones identified by Gunther et al, might be beneficial, depending on the therapeutic indication [2,14].…”