Selective Gene Regulation by Androgen Receptor in Prostate Cancer
Annual rept. 30 Sep 2012-Sep 2013
MICHIGAN UNIV ANN ARBOR MEDICAL CENTER
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Growth and development of the prostate is highly dependent on androgen, and aberrant androgen and androgen receptor AR signaling is the key driver in the pathology and progression of prostate cancer. Blocking androgen synthesis and inhibiting AR function is the first line of therapy for prostate cancer patients. Although this approach is initially effective in suppressing disease progression, castration resistant tumors eventually develop resulting from reactivation of AR activity. A novel approach to overcome resistance to therapy is to identify selective AR modulators SARMs that inhibit the expression of genes promoting tumor growth but enable the expression of genes for differentiation. We hypothesize that functionally distinct set of genes have different promoter signature marks that are recognized by AR. Re- testing and validation of several hits obtained from a high-throughput promoter-dependent compound screen of FDA approved drugs identified a lead compound that had a differential effect on AR promoter-element recognition in transient transfection assays, and in the expression of select AR target genes associated with proliferation and differentiation. Cell proliferation assays indicate that the compound is able to inhibit AR-dependent cell growth. Our discovery of this compound in an unbiased screen for SARMs provides proof-of-concept that drugs may be developed that differentially target promoter elements that distinguish pro-proliferation from pro-differentiation genes.
- Genetic Engineering and Molecular Biology
- Medicine and Medical Research