Cellular specificity of androgen receptor, coregulators, and pioneer factors in prostate cancer

Abstract

Androgen signalling, through the transcription factor androgen receptor (AR), is vital to all stages of prostate development and most prostate cancer progression. AR signalling controls differentiation, morphogenesis and function of the prostate. It also drives proliferation and survival in prostate cancer cells as the tumour progresses; given this importance it is the main therapeutic target for disseminated disease. AR is also essential in the surrounding stroma, for the embryonic development of the prostate and controlling epithelial glandular development. Stromal AR is also important in cancer initiation, regulating paracrine factors that excite cancer cell proliferation, but lower stromal AR expression correlates with shorter time to progression/worse outcomes. The profile of AR target genes is different between benign and cancerous epithelial cells, between castrate resistant prostate cancer cells (CRPC) and treatment naïve cancer cells, between metastatic and primary cancer cells, and between epithelial cells and fibroblasts. This is also true of AR DNA-binding profiles. Potentially regulating the cellular specificity of AR binding and action are pioneer factors and coregulators, which control and influence the ability of AR to bind to chromatin and regulate gene expression. The expression of these factors differs between benign and cancerous cells, as well as throughout disease progression. The expression profile is also different between fibroblast and mesenchymal cell types. The functional importance of coregulators and pioneer factors in androgen signalling makes them attractive therapeutic targets, but given the contextual expression of these factors, it is essential to understand their roles in different cancerous and cell-lineage states.

Phenotypic plasticity, spatial niches and cancer-associated fibroblast/mural cell interactions define the human prostate cancer microenvironment

“…Prostate pSMCs are also AR + and androgendependent. Notably however, AR knockout in prostate SMCs promotes fibrosis and exacerbates PCa progression 42 , indicating a tumor-suppressive role of AR signaling in SMCs. Accordingly, lower stromal AR levels and pSMC loss are associated with poor outcome, whereby intact layers of pSMCs may restrain tumor invasion 42 .…”

“…Notably however, AR knockout in prostate SMCs promotes fibrosis and exacerbates PCa progression 42 , indicating a tumor-suppressive role of AR signaling in SMCs. Accordingly, lower stromal AR levels and pSMC loss are associated with poor outcome, whereby intact layers of pSMCs may restrain tumor invasion 42 . Conversely, the PCa-myCAF phenotype is associated with hallmarks of poor prognosis and represented the dominant CAF subpopulation in clinical PCa and castration-resistant subpopulation in aggressive PDX models.…”

Liver Microenvironment Response to Prostate Cancer Metastasis and Hormonal Therapy

“…Androgen receptors are not just expressed in cancerous epithelial cells, but in multiple cell types of the prostate stroma [ 89 , 96 ]. Stromal AR is well documented to be essential for normal prostate growth and development [ 97 ].…”

Dissecting the effects of androgen deprivation therapy on cadherin switching in advanced prostate cancer: A molecular perspective

“…The term AR co-regulators represents a wide group of molecules that include proteins and RNAs that regulate AR activity [72] and the relationship between AR and co-regulators affects development, progression, and treatment outcome of PCa [103]. Indeed, AR co-regulators are differentially expressed in all stages of PCa including CRPC [104]. Furthermore, it has been suggested that differential expressions of AR coregulators contribute to the development of CRPC [105] and altered levels of co-activators and co-repressors result in induction of AR transcriptional activity in CRPC, even at extremely low concentrations of androgen [104].…”

“…Indeed, AR co-regulators are differentially expressed in all stages of PCa including CRPC [104]. Furthermore, it has been suggested that differential expressions of AR coregulators contribute to the development of CRPC [105] and altered levels of co-activators and co-repressors result in induction of AR transcriptional activity in CRPC, even at extremely low concentrations of androgen [104].…”