2088

Breast-Cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene that when mutated predispose women to breast and ovarian cancers. The BRCA1 protein participates in multiple functions, including DNA repair, transcription, and cell cycle control. Hereditary breast cancers account for up to 10% of all breast cancers, and inherited mutations of the BRCA1 gene account for about 45% of these hereditary cancers. Peroxisome proliferator-activated receptors (PPARs) are a member of the orphan nuclear receptor superfamily. There are three subtypes; PPARα, PPARβ/δ and PPARγ. While PPARα and PPARβ/δ are implicated in cell proliferation, activation of PPARγ has been shown to inhibit cell growth, inhibit aromatase activity in adipose tissue, inhibit estrogen receptor activity, and play a role in breast tumor regression. PPARγ ligands could be used as chemopreventive agents in women with familial breast cancer history. The role of PPARγ in breast cancer is evident, but the mechanism of action remains unclear. Studies have shown that rosiglitazone, a PPARγ ligand, significantly increased the endogenous nuclear levels of BRCA1 protein in MCF-7 cells. These results suggest that PPARγ could represent an important role in the molecular pathway for the regulation of BRCA1 gene expression. To evaluate the possibility of up-regulating BRCA1 gene expression in vivo, wild-type mice were administered a dose of 400 mg/kg rosiglitazone in the diet for two weeks. A control group received the same diet with no rosiglitazone supplementation. Mammary gland morphology will be examined using mammary gland whole mounts and hematoxylin and eosin staining. Real time RT-PCR will be used to study changes in BRCA1 gene expression in the mammary gland as well as other gene targets that could help us better understand chemopreventive properties of this type of agents. The long-range goal of this study is to identify genetic and molecular events in which PPARγ ligands might up-regulate BRCA1 gene expression to eventually translate these results to people. This approach introduces a promising new era of drug treatment in which patients that are screened genetically and exhibit predisposition for familial breast cancer could have the possibility of reducing the chances of developing breast cancer.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]