title: Farnesoid X receptor inhibits tamoxifen-resistant MCF-7 breast cancer cell growth through downregulation of HER2 expression.
abstract: Tamoxifen (Tam) treatment is a first-line endocrine therapy for estrogen receptor-α-positive breast cancer patients. Unfortunately, resistance frequently occurs and is often related with overexpression of the membrane tyrosine kinase receptor HER2. This is the rationale behind combined treatments with endocrine therapy and novel inhibitors that reduce HER2 expression and signaling and thus inhibit Tam-resistant breast cancer cell growth. In this study, we show that activation of farnesoid X receptor (FXR), by the primary bile acid chenodeoxycholic acid (CDCA) or the synthetic agonist GW4064, inhibited growth of Tam-resistant breast cancer cells (termed MCF-7 TR1), which was used as an in vitro model of acquired Tam resistance. Our results demonstrate that CDCA treatment significantly reduced both anchorage-dependent and anchorage-independent epidermal growth factor (EGF)-induced growth in MCF-7 TR1 cells. Furthermore, results from western blot analysis and real-time reverse transcription-PCR revealed that CDCA treatment reduced HER2 expression and inhibited EGF-mediated HER2 and p42/44 mitogen-activated protein kinase (MAPK) phosphorylation in these Tam-resistant breast cancer cells. Transient transfection experiments, using a vector containing the human HER2 promoter region, showed that CDCA treatment downregulated basal HER2 promoter activity. This occurred through an inhibition of nuclear factor-κB transcription factor binding to its specific responsive element located in the HER2 promoter region as revealed by mutagenesis studies, electrophoretic mobility shift assay and chromatin immunoprecipitation analysis. Collectively, these data suggest that FXR ligand-dependent activity, blocking HER2/MAPK signaling, may overcome anti-estrogen resistance in human breast cancer cells and could represent a new therapeutic tool to treat breast cancer patients that develop resistance.
authors.affiliation: Centro Sanitario, University of Calabria, Arcavacata di Rende, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Giordano
authors.forename: S
authors.initials: S
authors.lastname: Catalano
authors.forename: S
authors.initials: S
authors.lastname: Panza
authors.forename: D
authors.initials: D
authors.lastname: Vizza
authors.forename: I
authors.initials: I
authors.lastname: Barone
authors.forename: D
authors.initials: D
authors.lastname: Bonofiglio
authors.forename: L
authors.initials: L
authors.lastname: Gelsomino
authors.forename: P
authors.initials: P
authors.lastname: Rizza
authors.forename: S A W
authors.initials: SA
authors.lastname: Fuqua
authors.forename: S
authors.initials: S
authors.lastname: Andò
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002635:Chenodeoxycholic Acid / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D047369:Chromatin Immunoprecipitation; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000187:drug effects; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D018931:Antineoplastic Agents, Hormonal; D002635:Chenodeoxycholic Acid; D004815:Epidermal Growth Factor; D007555:Isoxazoles; D048052:Mitogen-Activated Protein Kinase 3; D016328:NF-kappa B; D018719:Erb-b2 Receptor Tyrosine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D013629:Tamoxifen; D000099150:Receptor, Farnesoid X-Activated; C508053:ERBB2 protein, human; C412815:GW 4064