Inhibition of Breast Cancer by Activating the Nuclear Receptor LXR

Description of projects available to graduate students:
Breast cancer results from overgrowth of the mammary epithelial cells. Estrogen (E2) is required for mammary epithelial proliferation and is a prerequisite for breast cancer formation. Estrogen can be deactivated by sulfation, a conjugation reaction that is catalyzed by the estrogen sulfotransferase (EST). The sulfonated E2 is inactive since it cannot bind to the estrogen receptor. EST is expressed in normal mammary epithelial cells but not in many breast cancer cell lines, suggesting it may play a role in breast cancer.

We hypothesize that EST is a transcriptional target of LXR. Activation of LXR induces the expression of EST and promotes estrogen deactivation, resulting in the inhibition of E2-dependent cell growth and tumorigenesis. The overall objective is to establish EST as a LXR target gene and to determine the implication of this gene regulation in estrogen homeostasis and breast cancer. The elucidation of the molecular pathways by which LXR regulate EST expression and estrogen deprivation may help to develop novel preventions and therapies for breast cancer.

For more information about our research, please http://www.pharmacology.us/Faculty/WenXie, or http://www.pharmacy.pitt.edu/directory/profile.lasso?Page=157&Type=Faculty

Representative Publications (* indicates graduate students in the lab):

1. *Uppal H, Saini SPS, Moschetta A, Mu Y, Zhou J, Gong H, Zhai Y, Ren S, Michalopoulos GK, Mangelsdorf DJ, and Xie W. Activation of LXRs prevents bile acid toxicity and cholestasis in female mice. Hepatology 45: 422-432 (2007).

2. *Uppal H, Zhai Y, Gangopadhyay A, Khadem S, Ren S, Moser JA, and Xie W. Activation of LXR sensitizes mice to gallbladder cholesterol crystallization. Hepatology 47: 1331-1342 (2008)

3. *Lee JH, Gong H, Khadem S, Lu Y, Gao X, Li S, Zhang J, Xie W. Androgen deprivation by activating the liver X receptor (LXR). Endocrinology 149: 3778-3788 (2008)

4. *Gao J, He J, Zhai Y, Wada T, Xie W. The constitutive androstane receptor is an anti-obesity nuclear receptor that improves insulin sensitivity. J Biol Chem. 284: 25984-25992 (2009)

5. *Lee JH, Wada T, Febbraio M, He J, Matsubara T, Lee MJ, Gonzalez FJ, Xie W. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology 139: 653-63 (2010)

6. *Ou Z, Wada T, Gramignoli R, Li S, Strom SC, Huang M, Xie W. MicroRNA hsa-miR-613 targets the human LXRα gene and mediates a feed-back loop of LXRα autoregulation. Mol Endocrinol 25: 584-96 (2011)

Techniques graduate student will learn:
Transient transfection and luciferase reporter gene assays; cloning and characterization of promoter sequences; use of transgenic and gene knockout mice