Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells

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 and Donald P. McDonnell ()
Additional contact information
Rachid Safi: Duke University School of Medicine
Suzanne E. Wardell: Duke University School of Medicine
Paige Watkinson: Duke University School of Medicine
Xiaodi Qin: Duke University School of Medicine
Marissa Lee: Duke University School of Medicine
Sunghee Park: Duke University School of Medicine
Taylor Krebs: Duke University School of Medicine
Emma L. Dolan: Duke University School of Medicine
Adam Blattler: Bristol Myers Squibb
Toshiya Tsuji: Bristol Myers Squibb
Surendra Nayak: Bristol Myers Squibb
Marwa Khater: Bristol Myers Squibb
Celia Fontanillo: Bristol Myers Squibb
Madeline A. Newlin: Duke University School of Medicine
Megan L. Kirkland: Duke University School of Medicine
Yingtian Xie: Dana-Farber Cancer Institute
Henry Long: Dana-Farber Cancer Institute
Emma C. Fink: Loyola University
Sean W. Fanning: Loyola University
Scott Runyon: RTI International
Myles Brown: Dana-Farber Cancer Institute
Shuichan Xu: Bristol Myers Squibb
Kouros Owzar: Duke University School of Medicine
John D. Norris: Duke University School of Medicine
Donald P. McDonnell: Duke University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52032-y

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