Androgen receptor monomers and dimers regulate opposing biological processes in prostate cancer cells
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.
Authors
- Marwa Khater (ORCID: https://orcid.org/0009-0002-5482-8711)
- Xiaodi Qin (ORCID: https://orcid.org/0000-0001-7066-8151)
- John D. Norris (ORCID: https://orcid.org/0000-0001-6553-8053)
- Emma Dolan (ORCID: https://orcid.org/0000-0003-1086-3275)
- Marissa R. Lee (ORCID: https://orcid.org/0000-0001-7188-9933)
- Kouros Owzar (ORCID: https://orcid.org/0000-0002-3340-1287)
- Myles A Brown (ORCID: https://orcid.org/0000-0002-8213-1658)
- Suzanne E. Wardell (ORCID: https://orcid.org/0000-0002-5792-1447)
- Sean William Fanning (ORCID: https://orcid.org/0000-0002-9428-0060)
- Adam Blattler (ORCID: https://orcid.org/0000-0002-4682-7201)
- Yingtian Xie (ORCID: https://orcid.org/0000-0003-0206-457X)
- Donald P. McDonnell (ORCID: https://orcid.org/0000-0002-7331-4700)
- Henry W. Long (ORCID: https://orcid.org/0000-0001-6849-6629)
- Celia Fontanillo (ORCID: https://orcid.org/0000-0002-3631-7881)
- Taylor Krebs
- Scott P. Runyon (ORCID: https://orcid.org/0000-0003-3113-8005)
- Surendra Kumar Nayak (ORCID: https://orcid.org/0000-0002-3544-8791)
- Emma C. Fink (ORCID: https://orcid.org/0009-0002-8506-0995)
- Madeline Newlin (ORCID: https://orcid.org/0009-0009-6862-4876)
- Rachid Safi
- Shuichan Xu (ORCID: https://orcid.org/0009-0001-9105-4199)
- Toshiya Tsuji (ORCID: https://orcid.org/0009-0005-6948-671X)
- Paige Watkinson
- Sunghee Park (ORCID: https://orcid.org/0000-0002-1447-4536)
- Megan L. Kirkland
Institutions
- Duke University (US)
- RTI International (US)
- Loyola University Chicago (US)
- Bristol-Myers Squibb (United States) (US)
- Dana-Farber Cancer Institute (US)
- Retina Vitreous Associates of Florida (US)
- Predictive Science (United States) (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-03
- DOI
- https://doi.org/10.1038/s41467-024-52032-y
- Citations
- 36
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 15.08
Funders
- North Carolina Biotechnology Center
- National Cancer Institute