Our long term objective is to understand why tamoxifen, an antiestrogen used in breast cancer treatment, in some circumstances behaves as an estrogen agonist and stimulates gene expression. Tamoxifen has tissue specific estrogen-like effects when estrogen receptor alpha (ERalpha) activates target genes regulated by AP-1 sites. Tamoxifen working through the newly discovered estrogen receptor beta (ERbeta) has even more powerful and tissue independent effects on target genes with AP-1 sites. We want to understand the mechanisms whereby ERs enhance the activity of such AP-1 target genes, why ERbeta is a super-enhancer, and the physiological role of such enhancement. These are our aims:
Aim 1. Investigate the hypothesis that both estrogen-bound and tamoxifen-bound ERs stimulate transcription from promoters regulated through AP-1 sites by enhancing the activity of the coactivator complex consisting of CBP and p160 proteins that Jun and Fos have recruited to the site.
Aim 2. Investigate the potential mechanisms whereby (A) estradiol-ERalpha and (B) tamoxifen-ERalpha enhance the activity of the CBP:p160 complex recruited by Jun/Fos.
Aim 3. Investigate why tamoxifen allows ERbeta, unlike ERalpha, to stimulate gene expression at AP-1 in breast cancer cells, and determine whether this action of ERbeta plays a role in the phenomenon of tamoxifen resistance during breast cancer progression.
Aim 4. Determine the physiological role of ER activation of AP-1 target genes in uterine and mammary development by studying mice in which we have replaced the gene for the wild type ERalpha with altered versions that are selectively defective or superactive at AP-1 sites depending on the ligand. If successful, these studies will lead to a understanding of the molecular mechanisms and physiological roles of ER action at AP-1 sites, neither of which are currently known. These studies will also have profound consequences for the development of a new generation of antiestrogens for breast cancer treatment and prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA080210-01
Application #
2752219
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Forry, Suzanne L
Project Start
1999-01-08
Project End
2002-11-30
Budget Start
1999-01-08
Budget End
1999-11-30
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Zavodovskaya, Marianna; Campbell, Michael J; Maddux, Betty A et al. (2008) Nordihydroguaiaretic acid (NDGA), an inhibitor of the HER2 and IGF-1 receptor tyrosine kinases, blocks the growth of HER2-overexpressing human breast cancer cells. J Cell Biochem 103:624-35
Hodges-Gallagher, Leslie; Valentine, Cathleen D; Bader, Suzy El et al. (2007) Inhibition of histone deacetylase enhances the anti-proliferative action of antiestrogens on breast cancer cells and blocks tamoxifen-induced proliferation of uterine cells. Breast Cancer Res Treat 105:297-309
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