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. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA117749-02
Application #
7287374
Study Section
Special Emphasis Panel (ZRG1-F09-S (20))
Program Officer
Jakowlew, Sonia B
Project Start
2006-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$27,315
Indirect Cost
Name
Medical University of South Carolina
Department
Pharmacology
Type
Schools of Medicine
DUNS #
183710748
City
Charleston
State
SC
Country
United States
Zip Code
29425
Mack, Jody T; Helke, Kristi L; Normand, Gabrielle et al. (2011) ABCA2 transporter deficiency reduces incidence of TRAMP prostate tumor metastasis and cellular chemotactic migration. Cancer Lett 300:154-61
Mack, Jody T; Beljanski, Vladimir; Soulika, Athena M et al. (2007) ""Skittish"" Abca2 knockout mice display tremor, hyperactivity, and abnormal myelin ultrastructure in the central nervous system. Mol Cell Biol 27:44-53