Androgen receptor functions as transcriptional repressor of Cancer Associated Fibroblast (CAF) activation [ChIP-seq]

The age-associated increase of cancer risk has been linked with stromal fibroblast senescence and early steps of Cancer Associated Fibroblast (CAF) activation. Surprisingly little is known about the role of androgen receptor (AR) signalling in this context. We show that AR expression is down-modulated in stromal fibroblasts underlying premalignant skin cancer lesions (actinic keratoses, AK) as well as in CAFs from the three major skin cancer types, squamous (SCC) and basal cell (BCC) carcinomas and melanomas. Decreased AR expression is linked to the concomitant down-modulation of CSL, key effector of canonical Notch signalling and global modulator of chromatin configuration, and it can be counteracted by treatment with BET inhibitors, which reverse CAF activation. Functionally, AR gene silencing in dermal fibroblasts results in p53-dependent senescence and induction of key CAF-effector genes, with AR physically converging with CSL in negative control of these genes. The findings are of functional significance as, in an orthotopic model of skin cancer, dermal fibroblasts with AR loss enhance significantly tumorigenicity of SCC and melanoma cells. As such, the findings establish AR as a novel potential target for stroma-focused cancer prevention and treatment.