Growth factors (GFs) play an important role in development and growth of mammary and endometrial cancer. Some evidence suggests that GFs and protein kinase (PK) inducers activate estrogen-dependent gene expression via estrogen receptor (ER)-dependent and -independent pathways. Moreover, preliminary studies show that 2,3,7,8-tetrchlorodibenzo-p-dioxin (TCDD), a prototypical aryl hydrocarbon receptor (AhR) agonist, inhibits GF/PK-ER crosstalk in MCF-7 human breast cancer cells. Therefore, Dr. Safe hypothesizes that (a) GF/PK-mediated induction of cathepsin D and c-fos protooncogene expression and cell growth involves both ER-dependent and -independent pathways and (b) AhR agonists (an important class of environmental contaminants) modulate GF/PK-ER crosstalk and can be used to probe the mechanism of interaction between the two signaling pathways. This proposed study will utilize Ah-responsive ER-positive MCF-7 and ER-negative MDA-MB-468 breast cancer cells, and selected AhR agonists. The following specific aims will test the validity of our hypothesis:
Aim 1 : The effects of GFs and PK inducers on cathepsin D gene expression will be thoroughly investigated in different cell types using wild-type and mutant ER expression plasmids.
This Aim will take advantage of ongoing studies which have identified three distinct estrogen-responsive promoter regions containing Sp1/ERE(1/2), Sp1 and imperfect palindromic ERE motifs (ES1, ES2 and ES3, respectively).
Aim 2 :
This Aim will utilize c-fos protooncogene and related promoter- reporter constructs as a second model for investigating GF/PK-ER crosstalk and the role of ER-dependent and -independent pathways of gene regulation. Previous studies have identified functional inhibitory dioxin responsive elements (iDREs) within the c-fos protooncogene and cathepsin D gene promoters, which are required for AhR-mediated antiestrogenicity.
Aim 3 will determine the mechanism of inhibition of GF-induced responses by AhR agonists.
Aim 4 will focus on GF-induced cell cycle enzymes and targeted inhibition by AhR agonists. The proposed studies will determine the mechanism of GF/PK-induced transactivation of c-fos and cathepsin D and delineate both ER-dependent and - independent pathways. The effects of AhR agonists will determine impacts of important dietary/environmental endocrine disruptors on these coupled endocrine pathways, which play important roles in development of hormone-dependent cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Research Project (R01)
Project #
5R01ES009253-02
Application #
6150733
Study Section
Reproductive Endocrinology Study Section (REN)
Program Officer
Heindel, Jerrold
Project Start
1999-02-01
Project End
2002-01-31
Budget Start
2000-02-01
Budget End
2001-01-31
Support Year
2
Fiscal Year
2000
Total Cost
$144,817
Indirect Cost
Name
Texas A&M University
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
047006379
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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