title: The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression.
abstract: 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.
authors.affiliation: Cardiac, Vascular and Inflammation Research, William Harvey Research Institute, Charterhouse Square, London EC1M 6BQ, United Kingdom.
authors.forename: Karen E
authors.initials: KE
authors.lastname: Swales
authors.forename: Márta
authors.initials: M
authors.lastname: Korbonits
authors.forename: Robert
authors.initials: R
authors.lastname: Carpenter
authors.forename: Desmond T
authors.initials: DT
authors.lastname: Walsh
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.forename: David
authors.initials: D
authors.lastname: Bishop-Bailey
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001141:Aromatase / Q000096:biosynthesis*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D006913:Hydroxysteroid Dehydrogenases / Q000096:biosynthesis / Q000235:genetics; D007555:Isoxazoles / Q000494:pharmacology; D008024:Ligands; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D014157:Transcription Factors / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific)
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D001141:Aromatase; D004268:DNA-Binding Proteins; D006913:Hydroxysteroid Dehydrogenases; D007555:Isoxazoles; D008024:Ligands; D000089762:Multidrug Resistance-Associated Protein 2; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C000715087:ABCC2 protein, human; C099713:nuclear receptor subfamily 0, group B, member 2; C435496:AKR1C2 protein, human; D045002:3-alpha-Hydroxysteroid Dehydrogenase (B-Specific); C412815:GW 4064