DEFINING THE CELLULAR AND PHYSIOLOGICAL ROLE OF ABCA2 - DESCRIPTION (provided by applicant): Overexpression of the ATP binding cassette (ABC) transporter, ABCA2, has been linked to resistance to estramustine, a drug used to treat hormone-refractory prostate cancer. ABCA2 has a putative role in trafficking cholesterol, steroids and lipids into endolysosomes, suggesting a role in human disease, including cancer and atherosclerosis. To date, forced over-expression of ABCA2 in cell lines has been the only tool used to investigate its function. The studies outlined in this proposal use ABCA2-knockout and -knock-in transgenic mice to examine the role of ABCA2 in cholesterol metabolism, physiology and prostate tumor development/treatment response in mice crossed to the TRAMP mouse model of prostate carcinoma. Mouse embryonic fibroblasts (MEFs), derived from knockout and knock-in mice, and prostate cancer cells (PCS, DU145, LNCaP), stably transfected with inducible ABCA2 expression or RNA interference, will be analyzed for response to changes in ABCA2 levels. Effects of ABCA2 expression on proliferation, cholesterol trafficking and drug treatment response will be examined. The ultimate goal is to understand the cellular and physiological function of ABCA2 using transgenic animal models, MEFs and human prostate cancer cells.
