Breast cancer is one of the leading causes of premature death in women and development of chemoprevention and chemotherapeutic interventions wilt require understanding of the important steps that lead to tumor formation, growth and metastasis. Estrogen receptor (ER)-positive and -negative breast cancer cells have been extensively used as models for studying signaling pathways that are important for breast tumor growth. Both 17beta-estradiol (E2) and polypeptide growth factors (GFs) have been identified as important mitogens for breast cancer cell growth. We hypothesize that ERalpha-dependent activation of nongenomic phosphatidyl inositol 3-kinase (PI3-K) and mitogen-activated protein kinase (MAPK) pathways by E2 are important for breast cancer cell proliferation, and the proposed studies will investigate the mechanisms of non-genomic activation by E2.
Aim 1 will focus on the role of ERalpha in activation of PI3-K and MAPK using ER-positive breast cancer cells (MCF-7 and ZR-75) and ER-negative (CHO and COS) cells as models. The domains of ERalpha required for activation of kinases and the importance of cell context will be determined in transient transfection studies. The mechanisms of non-genomic action of E2 and the role of specific kinases in mediating activation of PI3-K and MAPK will be investigated in Aim 2. The studies will also determine the biological significance of direct ERalpha interactions with Src-SH2, G proteins, the p85 regulatory subunit of PI3-K and the IGF-1 receptor.
Aim 3 will focus on downstream mechanisms of ERalpha-dependent activation of c-fos by kinases. Dominant negative p85, MAPKK and Src expression plasmids transiently or stably transfected into breast cancer cells will be used to investigate the contribution of the MAPK and PI3-K pathways to the mitogenic activity of E2 in breast cancer cells (in vitro) and mammary tumors in athymic nude mice bearing breast cancer cell xenografts. The in vitro mechanistic studies will also be complemented by research on the contributions of kinase activation by E2 on cell proliferation and tumor growth and thereby define potential therapeutic targets for treating breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009253-07
Application #
6935291
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Heindel, Jerrold
Project Start
1999-02-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
7
Fiscal Year
2005
Total Cost
$218,250
Indirect Cost
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
078592789
City
College Station
State
TX
Country
United States
Zip Code
77845
Li, Xiangrong; Zhang, Shu; Safe, Stephen (2006) Activation of kinase pathways in MCF-7 cells by 17beta-estradiol and structurally diverse estrogenic compounds. J Steroid Biochem Mol Biol 98:122-32
Zhang, S; Li, X; Burghardt, R et al. (2005) Role of estrogen receptor (ER) alpha in insulin-like growth factor (IGF)-I-induced responses in MCF-7 breast cancer cells. J Mol Endocrinol 35:433-47
Chen, Chien-Cheng; Lee, Wan-Ru; Safe, Stephen (2004) Egr-1 is activated by 17beta-estradiol in MCF-7 cells by mitogen-activated protein kinase-dependent phosphorylation of ELK-1. J Cell Biochem 93:1063-74
Qin, Chunhua; Samudio, Ismael; Ngwenya, Sharon et al. (2004) Estrogen-dependent regulation of ornithine decarboxylase in breast cancer cells through activation of nongenomic cAMP-dependent pathways. Mol Carcinog 40:160-70
Li, Xiangrong; Qin, Chunhua; Burghardt, Robert et al. (2004) Hormonal regulation of lactate dehydrogenase-A through activation of protein kinase C pathways in MCF-7 breast cancer cells. Biochem Biophys Res Commun 320:625-34
Ngwenya, Sharon; Safe, Stephen (2003) Cell context-dependent differences in the induction of E2F-1 gene expression by 17 beta-estradiol in MCF-7 and ZR-75 cells. Endocrinology 144:1675-85
Duan, Renqin; Xie, Wen; Li, Xiangrong et al. (2002) Estrogen regulation of c-fos gene expression through phosphatidylinositol-3-kinase-dependent activation of serum response factor in MCF-7 breast cancer cells. Biochem Biophys Res Commun 294:384-94
Qin, Chunhua; Nguyen, Thu; Stewart, Jessica et al. (2002) Estrogen up-regulation of p53 gene expression in MCF-7 breast cancer cells is mediated by calmodulin kinase IV-dependent activation of a nuclear factor kappaB/CCAAT-binding transcription factor-1 complex. Mol Endocrinol 16:1793-809
Castro-Rivera, E; Samudio, I; Safe, S (2001) Estrogen regulation of cyclin D1 gene expression in ZR-75 breast cancer cells involves multiple enhancer elements. J Biol Chem 276:30853-61
Xie, W; Duan, R; Safe, S (2001) Activation of adenosine deaminase in MCF-7 cells through IGF-estrogen receptor alpha crosstalk. J Mol Endocrinol 26:217-28

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