Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA072039-03
Application #
2733288
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Johnson, George S
Project Start
1996-09-01
Project End
2000-06-30
Budget Start
1998-08-25
Budget End
1999-06-30
Support Year
3
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Cincinnati
State
OH
Country
United States
Zip Code
45221

  Publications

Kojetin, Douglas J; Burris, Thomas P; Jensen, Elwood V et al. (2008) Implications of the binding of tamoxifen to the coactivator recognition site of the estrogen receptor. Endocr Relat Cancer 15:851-70
Yang, Jun; Singleton, David W; Shaughnessy, Elizabeth A et al. (2008) The F-domain of estrogen receptor-alpha inhibits ligand induced receptor dimerization. Mol Cell Endocrinol 295:94-100
Feng, Yuxin; Manka, David; Wagner, Kay-Uwe et al. (2007) Estrogen receptor-alpha expression in the mammary epithelium is required for ductal and alveolar morphogenesis in mice. Proc Natl Acad Sci U S A 104:14718-23
Wang, Yong; Chirgadze, Nickolay Y; Briggs, Stephen L et al. (2006) A second binding site for hydroxytamoxifen within the coactivator-binding groove of estrogen receptor beta. Proc Natl Acad Sci U S A 103:9908-11
Singleton, David W; Feng, Yuxin; Yang, Jun et al. (2006) Gene expression profiling reveals novel regulation by bisphenol-A in estrogen receptor-alpha-positive human cells. Environ Res 100:86-92
Singleton, David W; Feng, Yuxin; Chen, Yangde et al. (2004) Bisphenol-A and estradiol exert novel gene regulation in human MCF-7 derived breast cancer cells. Mol Cell Endocrinol 221:47-55
Singleton, David W; Feng, Yuxin; Burd, Craig J et al. (2003) Nongenomic activity and subsequent c-fos induction by estrogen receptor ligands are not sufficient to promote deoxyribonucleic acid synthesis in human endometrial adenocarcinoma cells. Endocrinology 144:121-8
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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