Grant: Operating Grant

Introduction - Androgens are steroid hormones produced and secreted by the testes that have been strongly implicated in prostate cancer. These hormones act by activating a protein inside the cell called the androgen receptor (AR). AR regulates specific target genes and promotes tumor growth through protein interactions with AR cofactors. Abnormal expression and function of AR cofactors was suggested promote prostate cancer progression from the androgen-sensitive into the advanced androgen-insensitive stage, for which no curative option is available. We recently found two such cofactors, called PSF and p54nrb, inhibit AR functions regardless the presence of androgens. The hypothesis of this proposal is that PSF and p54nrb play important roles on AR functions and contribute to prostate cancer progression to the advanced androgen-insensitive state. Project description - To test these hypotheses, we will 1) define whether changes in protein levels of PSF and p54nrb affect prostate cancer growth and measure the protein levels of PSF and p54nrb in tissue samples from prostate cancer patients; 2) investigate whether changes in the activities of PSF and p54nrb impact on AR function; and 3) determine whether PSF and p54nrb regulate the expression of the AR regulated gene, clusterin. Clusterin was shown to enable prostate cancer become resistant to anti-cancer therapies. Significance - Current therapy is only effective for androgen sensitive prostate cancer, and no cure is available when prostate cancer develops into the advance state that is androgen insensitive. Treatments that block AR function would benefit both androgen-sensitive and insensitive prostate cancer. Studies from this proposal would establish whether PSF and p54nrb can be served as novel exciting targets to control AR function in prostate cancer, providing an urgently needed alternative to current anti-androgen therapy.