Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells
Rachid Safi, Suzanne E. Wardell, Paige Watkinson, Xiaodi Qin, Marissa R. Lee, Sunghee Park, Taylor Krebs, Emma Dolan, Adam Blattler, Toshiya Tsuji, Surendra Kumar Nayak, Marwa Khater, Celia Fontanillo, Madeline Newlin, Megan L. Kirkland, Yingtian Xie, Henry W. Long, Emma C. Fink, Sean W. Fanning, Scott P. Runyon, Myles Brown, Shuichan Xu, Kouros Owzar, John D. Norris, Donald P. McDonnell
Abstract
Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies. The response of prostate cancer cells to androgens depends on the dose. Here, the authors show that low levels of androgens function through androgen receptor (AR) monomers to activate mTOR and promote cell proliferation, while high dose androgens induce AR dimerization to inhibit c-MYC expression and facilitate cell differentiation.