The long-term goal of these studies is to develop therapeutic strategies to treat or prevent breast cancer. Since our demonstration that the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed and functionally active in breast cancer cells, a rapidly growing body of evidence has accumulated indicating that PPARgamma plays a central role in many types of cancer including breast cancer. Ligands include the antidiabetic thiazolidinediones, prostaglandin J2, fatty acids, and others. Treating breast cancer cells with PPARgamma ligands have alternatively been reported to induce cell cycle withdrawal, apoptosis, or mediate the expression of genes leading to a more differentiated, less malignant state. Other ligands, including fatty acids, have been reported to mediate the expression of genes that alter the malignancy and metastatic potential of breast cancer cells. The mechanism underlying these divergent actions has not been established. We have recently reported that the expression of ERalpha inhibits PPARgamma transactivation. Thus we will test the hypothesis that selective transactivation of PPARgamma by different ligands mediates gene expression profiles that favor either differentiation or proliferation, depending on the specific ligand used and the functional status of the ER in the same cells. Therefore, in Specific Aim 1 we will test the hypothesis that different PPARgamma ligands induce conformational changes that result in selective regulation of gene expression profiles and physiological responses in normal epithelia and in breast cancer cells.
In Specific Aim 2 we will examine the necessity of PPARgamma in mediating the gene expression profiles involved in proliferation, differentiation, and apoptosis.
In Specific Aim 3, we will examine the mechanism whereby the estrogen receptor alters the transactivation of PPARgamma and examine the physiological consequences of this interaction. This represents a novel approach to understanding the role PPARy plays in breast cancer and its selective modulation could point to novel mechanisms of action and to therapeutic targets.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA095609-03
Application #
7104839
Study Section
Biochemical Endocrinology Study Section (BCE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2004-08-05
Project End
2008-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
3
Fiscal Year
2006
Total Cost
$226,546
Indirect Cost
Name
University of Kentucky
Department
Pharmacology
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Zaytseva, Yekaterina Y; Wallis, Natalie K; Southard, R Chase et al. (2011) The PPARgamma antagonist T0070907 suppresses breast cancer cell proliferation and motility via both PPARgamma-dependent and -independent mechanisms. Anticancer Res 31:813-23
Al-Alem, Linah; Southard, R Chase; Kilgore, Michael W et al. (2011) Specific thiazolidinediones inhibit ovarian cancer cell line proliferation and cause cell cycle arrest in a PPAR? independent manner. PLoS One 6:e16179
Zaytseva, Yekaterina Y; Wang, Xin; Southard, R Chase et al. (2008) Down-regulation of PPARgamma1 suppresses cell growth and induces apoptosis in MCF-7 breast cancer cells. Mol Cancer 7:90
Talbert, Dominique R; Allred, Clinton D; Zaytseva, Yekaterina Y et al. (2008) Transactivation of ERalpha by Rosiglitazone induces proliferation in breast cancer cells. Breast Cancer Res Treat 108:23-33
Allred, Clinton D; Talbert, Dominique R; Southard, R Chase et al. (2008) PPARgamma1 as a molecular target of eicosapentaenoic acid in human colon cancer (HT-29) cells. J Nutr 138:250-6
Wang, Xin; Southard, R Chase; Allred, Clinton D et al. (2008) MAZ drives tumor-specific expression of PPAR gamma 1 in breast cancer cells. Breast Cancer Res Treat 111:103-11
Allred, Clinton D; Kilgore, Michael W (2005) Selective activation of PPARgamma in breast, colon, and lung cancer cell lines. Mol Cell Endocrinol 235:21-9