Investigating Steroid Receptor Coactivator 3 (SRC3) as a Potential Therapeutic Target for Treating Advanced Prostate Cancer

Abstract

Abstract : Prostate cancer is a major health concern in the United State and understanding the molecular biology underlying the development of prostate cancer can help improve the disease prevention and therapeutic strategies. Steroid receptor coactivator 3 (SRC-3) is a nuclear receptor coactivator that is important for growth of endocrine tissues. SRC-3 enhances proliferation of prostate cancer cell lines in a cellautonomous manner and its expression is highly correlated with aggressiveness of human prostate cancer tumor samples. Here I use animal models to study the function of SRC-3 in prostate cancer and ascertain the role of SRC-3 in a cell-type specific manner by employing the lox-Cre knockout system. In the first part of my research funding period, I aimed to determine whether SRC-3 promotes prostate tumor progression in cancer derived from luminal epithelial cells (LECs) by simultaneously deleting the Pten and SRC-3 genes in the LECs of the mouse prostate. I also assessed the function of SRC-3 in castration resistant prostate cancer (CRPC) by performing androgen deprivation experiments on this mouse model. I found that deletion of SRC-3 caused impairment of cellular proliferation translating into a progressive decrease in tumor size. While double knockout tumors did not histologically appear less disorganized or invasive, they exhibited a relative increase in basal-like and decrease in luminal-like cells. When I performed androgen-deprivation assay, I found that castration induces significant changes in the phenotype of tumors evidenced by cellular de-differentiation and stromal reactivity. SRC-3 deletion results in reversal of the castration-induced changes accompanied by a decreased S6 kinase in the tumor indicating a decrease in cellular translational output. This result provides a potential mechanistic link between SRC-3 absence and decreased tumor growth. In summary, SRC-3 controls the size of the prostate tumor and is a critical mediator in the development of CRP