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Sustained androgen receptor signaling is a determinant of melanoma cell growth potential and tumorigenesis.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2021 Feb 01; Vol. 218 (2). - Publication Year :
- 2021
-
Abstract
- Melanoma susceptibility differs significantly in male versus female populations. Low levels of androgen receptor (AR) in melanocytes of the two sexes are accompanied by heterogeneous expression at various stages of the disease. Irrespective of expression levels, genetic and pharmacological suppression of AR activity in melanoma cells blunts proliferation and induces senescence, while increased AR expression or activation exert opposite effects. AR down-modulation elicits a shared gene expression signature associated with better patient survival, related to interferon and cytokine signaling and DNA damage/repair. AR loss leads to dsDNA breakage, cytoplasmic leakage, and STING activation, with AR anchoring the DNA repair proteins Ku70/Ku80 to RNA Pol II and preventing RNA Pol II-associated DNA damage. AR down-modulation or pharmacological inhibition suppresses melanomagenesis, with increased intratumoral infiltration of macrophages and, in an immune-competent mouse model, cytotoxic T cells. AR provides an attractive target for improved management of melanoma independent of patient sex.<br />Competing Interests: Disclosures: R. Dummer had intermittent, project-focused consulting and/or advisory relationships with Novartis, Merck Sharp & Dhome (MSD), Bristol-Myers Squibb (BMS), Roche, Amgen, Takeda, Pierre Fabre, Sun Pharma, Sanofi, Catalym, Second Genome, Regeneron, and Alligator outside the submitted work. No other disclosures were reported.<br /> (© 2020 Ma et al.)
- Subjects :
- Animals
Carcinogenesis pathology
Cell Line, Tumor
DNA Damage genetics
DNA Repair genetics
Down-Regulation genetics
Female
Gene Expression Regulation, Neoplastic genetics
Humans
Male
Melanoma pathology
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, SCID
RNA Polymerase II genetics
Carcinogenesis genetics
Cell Proliferation genetics
Melanoma genetics
Receptors, Androgen genetics
Signal Transduction genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 218
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 33112375
- Full Text :
- https://doi.org/10.1084/jem.20201137