Androgen Signaling in the Tumor Microenvironment

The key function of mesenchymal/stromal androgen receptor (AR) signaling for prostate development has been well documented by tissue recombination experiments. Some studies have addressed the expression and function of AR in stromal cells in prostate cancer, yet our understanding of the role of stromal AR in other tissues beyond prostate is still insufficient. Genomic analysis has revealed that cellular responses to androgens differ between epithelial and stromal cells. AR in stromal cells seems not to act via classical AR transcription factors such as FOXA1 but rather depends on the JUN/AP1 complex. Stromal AR appears to have tumor-promoting and tumor-protective functions depending on tumor stage. Loss of AR signaling in fibroblasts has been detected already in premalignant lesions in the skin and prostate and has been associated with tumor induction in xenografts of skin cancer and aggressive disease features and poor patient prognosis in prostate cancer. Moreover, AR expression is found on virtually all tissue-infiltrating immune cells and plays critical roles in immune cell function. These findings suggest a potential deleterious impact of current androgen deprivation therapies which inhibit both epithelial and stromal AR, highlighting the need to develop tissue-specific AR inhibitors.