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The Farnesoid X Receptor Is Expressed in Breast Cancer and Regulates Apoptosis and Aromatase Expression

¹ Cardiac, Vascular and Inflammation Research; ² Department of Endocrinology, William Harvey Research Institute, Barts and the London, Queen Mary University of London; ³ Barts and the London Breast Care Centre, St. Bartholomew's Hospital; and ⁴ Department of Cellular and Molecular Neuroscience, Division of Neurosciences and Mental Health, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Charing Cross Hospital, London, United Kingdom

Requests for reprints: David Bishop-Bailey, Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, United Kingdom. Phone: 44-207-882-5785; Fax: 44-207-882-6104; E-mail: d.bishop-bailey{at}qmul.ac.uk.

Bile acids are present at high concentrations in breast cysts and in the plasma of postmenopausal women with breast cancer. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily that regulates bile acid homeostasis. FXR was detected in normal and tumor breast tissue, with a high level of expression in ductal epithelial cells of normal breast and infiltrating ductal carcinoma cells. FXR was also present in the human breast carcinoma cells, MCF-7 and MDA-MB-468. Activation of FXR by high concentrations of ligands induced MCF-7 and MDA-MB-468 apoptosis. At lower concentrations that had no direct effect on viability, the FXR agonist GW4064 induced expression of mRNA for the FXR target genes, small heterodimer partner (SHP), intestinal bile acid binding protein, and multidrug resistance–associated protein 2 (MRP-2), and repressed the expression of the SHP target gene aromatase. In contrast to MRP-2, mRNA for the breast cancer target genes MDR-3, MRP-1, and solute carrier transporter 7A5 were decreased. Although multidrug resistance transporters were regulated and are known FXR target genes, GW4064 had no effect on the cell death induced by the anticancer drug paclitaxel. Our findings show for the first time that FXR is expressed in breast cancer tissue and has multiple properties that could be used for the treatment of breast cancer. (Cancer Res 2006; 66(20): 10120-6)

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