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This version published online on May 29, 2007
Molecular Endocrinology, doi:10.1210/me.2007-0187
Molecular Endocrinology Vol. 0, No. 2007 200701871-
doi:10.1210/me.2007-0187
Copyright © 2007 by the Endocrine Society.
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*Breast Cancer

Submitted on April 13, 2007
Accepted on May 22, 2007

Estrogen Deprivation and Inhibition of Breast Cancer Growth in vivo through Activation of the Orphan Nuclear Receptor LXR

Haibiao Gong, Ping Guo, Yonggong Zhai, Jie Zhou, Hirdesh Uppal, Michael J. Jarzynka, Wenchao Song, Shiyuan Cheng, and Wen Xie*

Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261; University of Pittsburgh Cancer Institute and Department of Pathology, Pittsburgh, Pennsylvania 15213; Biomedicine Research Institute, Beijing Normal University, Beijing 100875, China; Institute for Translational Medicine and Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

* To whom correspondence should be addressed. E-mail: wex6{at}pitt.edu.

Estrogen plays an important role in normal physiology. It is also a risk factor for breast cancer and anti-estrogen therapies have been shown to be effective in the treatment and prevention of breast cancers. The liver is important for estrogen metabolism and a compromised liver function has been linked to hyperestrogenism in patients. In this report, we showed that the liver X receptor (LXR) controls estrogen homeostasis by regulating the basal and inducible hepatic expression of estrogen sulfotransferase (Est, or Sult1e1), an enzyme critical for metabolic estrogen deactivation. Genetic or pharmacological activation of LXR resulted in Est induction, which in turn inhibited estrogen-dependent uterine epithelial cell proliferation and gene expression, as well as breast cancer growth in a nude mouse model of tumorigenicity. We further established that Est is a transcriptional target of LXR and deletion of the Est gene in mice abolished the LXR effect on estrogen deprivation. Interestingly, Est regulation by LXR appeared to be liver-specific, further underscoring the role of liver in estrogen metabolism. Activation of LXR failed to induce other major estrogen metabolizing enzymes, suggesting that the LXR effect on estrogen metabolism is Est-specific. In summary, our results have revealed a novel mechanism controlling estrogen homeostasis in vivo and may have implications for drug development in the treatment of breast cancer and other estrogen-related cancerous endocrine disorders.
Key words: estrogen homeostasis • gene regulation • orphan nuclear receptor • sulfation • transgenic mice

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRα  |  RXRα
Ligands:   22α-Hydroxycholesterol  |  T0901317  |  GW 3965  |  17β-Estradiol



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