Androgen receptors (AR) are regulators of cell proliferation in the prostate. Antiandrogens can initially antagonize androgen dependent growth and inhibit tumor growth. Virtually all-prostate cancers become androgen-independent and androgen antagonists are converted to agonists. Androgen receptor is expressed in most androgen-independent prostate cancers, and may play a major role in the enhanced proliferation of resistant prostate cancer calls. I hypothesize that, analogous to the case of estrogen receptor, that N-CoR complex is the critical requirement for selective androgen receptor modulators (SARMs) to exert an inhibitory, rather than an activating function. I will utilize genetic and biochemical tools to test his hypothesis, investigating whether AR prevents recruitment or function of the corepressors and inhibits specific AR coregulatory complexes. To investigate the role of nuclear receptor coregulators in the conversion from antagonists to agonists in the transition to resistance, I will use in vitro and in vivo assays. This involves transfection and gene transcription assays, mouse gene knockout models, and chromatin immunoprecipitation analysis (ChIP) and single cell nuclear microinjection methodologies. I will use both RNA profiling and ChIP assays to examine whether SARMs activate all or only a subset of the androgen receptor-dependent programs in """"""""resistant"""""""" prostate cells and confirm the role of N-CoR. Understanding the molecular mechanisms that alter regulation of AR cofactor recruitment should provide new approaches to diagnosis and therapy of prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32CA105670-03
Application #
7121259
Study Section
Special Emphasis Panel (ZRG1-F09 (20))
Program Officer
Lohrey, Nancy
Project Start
2004-09-01
Project End
2007-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
3
Fiscal Year
2006
Total Cost
$52,048
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093