Unveiling the Role of the Androgen Receptor in Breast Cancer: A Comprehensive Clinical and Physiological Perspective

Abstract

Breast cancer (BC) is the most prevalent type of cancer worldwide. Although there are several therapeutic approaches available to treat BC, resistance arises regularly, indicating the urgent need for innovative therapeutics. The androgen receptor (AR) has shown promise as a key target in estrogen receptor alpha-positive (ER+)/AR+ BC treatment, owing to its reported antiproliferative effects. Selective Androgen Receptor Modulators (SARMs), such as RAD140, have emerged as a unique strategy without the limitations of natural androgens. In this study, we investigated the antiproliferative effects of RAD140 using the ER+/AR+ MCF-7 BC cell line. Our findings revealed that RAD140 activates AR without impacting the expression of other hormone receptors (ER and PR) or known ER co-activators and pioneer factors. Notably, prolonged RAD140 exposure led to a significant increase in AR expression, potentially contributing to the observed antiproliferative effect. To understand the functional crosstalk between ER and AR, we unveiled a novel mechanism involving liganded ER directly binding to regulatory regions in the AR gene upon 17ß-estradiol (E2) treatment. This binding resulted in the recruitment of histone deacetylase HDAC1 and ER to a specific 2 kb-long element, leading to reduced AR expression at both transcript and protein levels through alterations in H3K27ac and H3K18ac. Furthermore, we discovered that knockdown of AR in MCF-7 cells enhanced ER function, resulting in increased expression of ER target genes and E2-dependent cell proliferation. These findings suggest that AR may function as a tumor suppressor in BC. Activation of AR by RAD140 or its downregulation by E2 under physiological conditions appears to govern the progression and growth of BC. This research sheds light on the potential of targeting the androgen receptor as a therapeutic strategy for ER+/AR+ breast cancer. Understanding the intricate interactions between ER and AR could lead to the development of new treatment modalities aimed at overcoming resistance and improving patient outcomes.