Initiation, progression and metastasis of prostate cancer are greatly influenced by the state of the steroid hormone, androgen. These cancers usually start out as a hormone-dependent tumor and then gradually progress to a hormone-independent state at late stages. Mutation and/or alteration of the expression levels of androgen receptor have been implicated in the disease process. Since coactivators, such as SRCs, are integral parts of steroid receptor action, it is likely that they also play a role in prostate cancer formation, progression and metastasis. Indeed, our preliminary results and a recent report indicate that SRC-1 and -2 and -3 are overexpressed in prostate cancer patients. We hypothesize that the expression and/or activity of coactivators is elevated in prostate cancer cells and that this contributes to prostate cancer growth and progression. Consequently, we predict that administration of an antagonist of coactivator action will inhibit prostate cancer growth; thus, they represent a novel therapeutic target. In this proposal, we will extend our preliminary studies and examine the expression pattern of steroid receptor coactivators in prostate tumor samples and assess the potential of using them as prognostic markers for prostate cancer. In addition, we will seek to identify and characterize peptide antagonists that will inhibit SRC dependent and AR dependent prostate cancer growth. We believe the combined approaches proposed here are the best for us to understand the cause of some form of prostate cancers, identify markers for prognosis and devise a way to treat prostate cancers especially those refractory to hormone treatment. Accordingly, our specific aims are 1: Analysis of the expression pattern of steroid receptor coactivators, SRCs, and other coactivators in prostate cancer patients and correlation with other markers of tumor growth and progression. 2. Development of coactivator peptide antagonists that inhibit SRC-3, -1 and AR function. 3. Evaluation the effect of peptide antagonists on the growth of prostate cells in vitro and in vivo.
Showing the most recent 10 out of 262 publications
