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.
Highlights
Malignant melanoma is the fifth most common cancer in the world, and its incidence is rising
Immunostaining of cultured cells showed a variation in androgen receptor (AR) protein expression among various melanoma cell lines and primary melanoma cells derived from male or female patients, with AR levels being uniformly low in primary melanocytes (Fig. 1 E, Fig. S1 G, and Table S2)
A number of reports indicate that DNA damage can be induced in prostate cancer cells by overstimulation of AR activity (Chatterjee et al, 2019; Lin et al, 2009)
Summary
Malignant melanoma is the fifth most common cancer in the world, and its incidence is rising. Among the many prognostic risk factors that have been proposed for the disease, one of the most intriguing and least understood is sex (Nosrati and Wei, 2014). Melanoma is an example of primary clinical significance for investigating sex-related differences in cancer incidence and survival, with the male population having greater susceptibility than the female, across all ages (Nosrati and Wei, 2014). As for sexual dimorphism in other cancer types (Clocchiatti et al, 2016), even for susceptibility to melanoma, differences in sex hormone levels and/or downstream pathways are likely to play a key role (Nosrati and Wei, 2014). The great majority of accrued information for melanoma relates to estrogen signaling, while much less is known about androgen signaling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
