This proposal addresses the hypothesis that naturally occurring mutations in estrogen receptor (ER) affect ER dimerization, interaction with other cellular proteins, and transcriptional activity. Using the yeast two hybrid system, the applicant has previously shown that estrogen induces dimerization of the wtER protein and that the antiestrogens, tamoxifen and ICI 182,780, disrupt estrogen-induced dimerization of wtER. This proposal will extend these studies to ER, its variants, and two estrogen receptor associated proteins via four specific aims using the yeast two hybrid system. In the first aim the ability of estrogen to induce dimerization of variant/mutant ER as well as the effects of antiestrogens on this process will be explored.
Aim 2 will ascertain if deletion or point ER mutants affect the transcriptional activity of the wtER in the presence and absence of estrogen and antiestrogens.
In aim 3 the interaction of two estrogen receptor associated proteins, ERAP140 and RIP140, with wtER and with each other in the presence and absence of ligand will be studied.
In aim 4 the interactions between several ER variants/mutants and ERAP140 or RIP140 will be examined. These studies should help to address the molecular mechanisms leading to development and progression of hormone resistance in breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072039-02
Application #
2443308
Study Section
Reproductive Endocrinology Study Section (REN)
Project Start
1996-09-01
Project End
2000-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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Sheeler, Cameron Q; Singleton, David W; Khan, Sobhaib A (2003) Mutation of serines 104, 106, and 118 inhibits dimerization of the human estrogen receptor in yeast. Endocr Res 29:237-55
Puga, A; Barnes, S J; Chang, C et al. (2000) Activation of transcription factors activator protein-1 and nuclear factor-kappaB by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Biochem Pharmacol 59:997-1005
Dudley, M W; Sheeler, C Q; Wang, H et al. (2000) Activation of the human estrogen receptor by the antiestrogens ICI 182,780 and tamoxifen in yeast genetic systems: implications for their mechanism of action. Proc Natl Acad Sci U S A 97:3696-701

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