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.
Nature communications. 2024 Sep 03*** epublish ***
Rachid Safi, Suzanne E Wardell, Paige Watkinson, Xiaodi Qin, Marissa Lee, Sunghee Park, Taylor Krebs, Emma L Dolan, Adam Blattler, Toshiya Tsuji, Surendra Nayak, Marwa Khater, Celia Fontanillo, Madeline A Newlin, Megan L Kirkland, Yingtian Xie, Henry Long, Emma C Fink, Sean W Fanning, Scott Runyon, Myles Brown, Shuichan Xu, Kouros Owzar, John D Norris, Donald P McDonnell
Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA., Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA., Oncogenesis Thematic Research Center, Bristol Myers Squibb, San Diego, CA, USA., Informatics and Predictive Sciences, Bristol Myers Squibb, San Diego, CA, USA., Dana-Farber Cancer Institute, Boston, MA, USA., Department of Cancer Biology, Loyola University, Maywood, IL, USA., RTI International, Research Triangle Park, NC, USA., Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. .