Molecular regulation of estrogen receptors and recent advances on ERα36 splice variant in prostate cancer

Abstract

Prostate cancer is the second most common cause of cancer in men worldwide and first-line therapies for metastatic disease include androgen deprivation therapy and androgen receptor pathway inhibitors, in addition to chemotherapy for selected patients. Although these strategies improve patient prognosis, progression to castration-resistant prostate cancer (CRPC) and therapeutic resistance remain clinically significant. In this review will explore published and new evidence of the expression and function of estrogen receptors (ERs) ERα and ERβ, as well as their variants, and the G protein–coupled estrogen receptor (GPER) in normal prostate gland, during development and adulthood and in prostate cancer cell lines. Consistent with these findings, studies from the literature have demonstrated that ERα, ERβ, GPER are expressed in a cell-specific manner in the normal prostate gland. In the androgen-independent prostate cancer cells PC-3 (derived from bone metastasis) and DU-145 (brain metastasis), used in vitro and in xenograft implants as CRPC models, ERα and ERβ are present at transcript and protein levels, as well as the GPER. Importantly the presence of ERα36 splice variant is also detected in prostate cancer cells. Although the exact contributions of these modifications to prostate cancer advancement and treatment outcomes remain under investigation, the absence of selective inhibitors for the resulting ER variant proteins restricts deeper inquiry. Developing such targeted agents is crucial to uncovering variant biology in both healthy and malignant tissues, evaluating their therapeutic value in preclinical settings, and ultimately guiding clinical management.