| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Center for Pharmacogenetics and Department of Pharmaceutical Sciences (H.G., Y.Z., J.Z., H.U., W.X.), University of Pittsburgh, Pittsburgh, Pennsylvania 15261; University of Pittsburgh Cancer Institute and Department of Pathology (P.G., M.J.J., S.-Y.C.), Pittsburgh, Pennsylvania 15213; Biomedicine Research Institute (Y.Z.), Beijing Normal University, Beijing 100875, China; and Institute for Translational Medicine and Therapeutics and Department of Pharmacology (W.-C.S.), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Dr. Wen Xie, Center for Pharmacogenetics, University of Pittsburgh, Pittsburgh, Pennsylvania 15261. E-mail: wex6{at}pitt.edu.
Estrogen plays an important role in normal physiology. It is also a risk factor for breast cancer, and antiestrogen 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.
NURSA Molecule Pages Link:
This article has been cited by other articles:
 |
|
 |
|
  R. Geyeregger, M. Shehata, M. Zeyda, F. W. Kiefer, K. M. Stuhlmeier, E. Porpaczy, G. J. Zlabinger, U. Jager, and T. M. Stulnig Liver X receptors interfere with cytokine-induced proliferation and cell survival in normal and leukemic lymphocytes J. Leukoc. Biol., November 1, 2009; 86(5): 1039 - 1048. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. W. Christopherson II and A. Landay Editorial: Liver X receptor {alpha} (LXR{alpha}) as a therapeutic target in chronic lymphocytic leukemia (CLL) J. Leukoc. Biol., November 1, 2009; 86(5): 1019 - 1021. [Full Text] [PDF]
|
|
|
|
 |
|
 W.-K. Kim, V. Meliton, K. W. Park, C. Hong, P. Tontonoz, P. Niewiadomski, J. A. Waschek, S. Tetradis, and F. Parhami Negative Regulation of Hedgehog Signaling by Liver X Receptors Mol. Endocrinol., October 1, 2009; 23(10): 1532 - 1543. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Mouzat, F. Volat, S. Baron, G. Alves, A. J. C. Pommier, D. H. Volle, G. Marceau, A. DeHaze, P. Dechelotte, R. Duggavathi, et al. Absence of Nuclear Receptors for Oxysterols Liver X Receptor Induces Ovarian Hyperstimulation Syndrome in Mice Endocrinology, July 1, 2009; 150(7): 3369 - 3375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L.-L. Vedin, S. A. Lewandowski, P. Parini, J.-A. Gustafsson, and K. R. Steffensen The oxysterol receptor LXR inhibits proliferation of human breast cancer cells Carcinogenesis, April 1, 2009; 30(4): 575 - 579. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. K. Khor, M. H. Tong, Y. Qian, and W.-C. Song Gender-Specific Expression and Mechanism of Regulation of Estrogen Sulfotransferase in Adipose Tissues of the Mouse Endocrinology, November 1, 2008; 149(11): 5440 - 5448. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Wada, H. S. Kang, A. M. Jetten, and W. Xie The Emerging Role of Nuclear Receptor ROR{alpha} and Its Crosstalk with LXR in Xeno- and Endobiotic Gene Regulation Experimental Biology and Medicine, October 1, 2008; 233(10): 1191 - 1201. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Gong, M. J. Jarzynka, T. J. Cole, J. H. Lee, T. Wada, B. Zhang, J. Gao, W.-C. Song, D. B. DeFranco, S.-Y. Cheng, et al. Glucocorticoids Antagonize Estrogens by Glucocorticoid Receptor-Mediated Activation of Estrogen Sulfotransferase Cancer Res., September 15, 2008; 68(18): 7386 - 7393. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Hoon Lee, H. Gong, S. Khadem, Y. Lu, X. Gao, S. Li, J. Zhang, and W. Xie Androgen Deprivation by Activating the Liver X Receptor Endocrinology, August 1, 2008; 149(8): 3778 - 3788. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Wada, H. S. Kang, M. Angers, H. Gong, S. Bhatia, S. Khadem, S. Ren, E. Ellis, S. C. Strom, A. M. Jetten, et al. Identification of Oxysterol 7{alpha}-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor {alpha} (ROR{alpha}) (NR1F1) Target Gene and a Functional Cross-Talk between ROR{alpha} and Liver X Receptor (NR1H3) Mol. Pharmacol., March 1, 2008; 73(3): 891 - 899. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, A. Wilson, R. Kuruba, Q. Zhang, X. Gao, F. He, L.-M. Zhang, B. R. Pitt, W. Xie, and S. Li FXR-mediated regulation of eNOS expression in vascular endothelial cells Cardiovasc Res, January 1, 2008; 77(1): 169 - 177. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
