title: Down-regulation of Forkhead box protein A1 (FOXA1) leads to cancer stem cell-like properties in tamoxifen-resistant breast cancer cells through induction of interleukin-6.
abstract: The selective estrogen receptor (ER) modulator tamoxifen inhibits ER signaling in breast cancer cells, and it is used for the treatment of ER-positive breast cancer. However, this type of cancer often acquires resistance to tamoxifen, and a better understanding of the molecular mechanisms underlying tamoxifen resistance is required. In this study, we established tamoxifen-resistant (TAM-R) breast cancer cells by long-term tamoxifen treatment of ER-positive breast cancer MCF7 cells. In TAM-R cells, expression of not only ERα, a major form of ER in breast cancer, but also its transcriptional partner forkhead box protein A1 (FOXA1) was found to be reduced. In contrast, activation of the transcription factor nuclear factor-κB (NF-κB) and expression of its targetIL6were increased in these cells. Stable expression of FOXA1, but not ERα, reduced the expression ofIL6in the FOXA1- and ERα-negative breast cancer MDA-MB-231 cells and TAM-R cells, without affecting the activation of the NF-κB signaling pathways. Conversely, FOXA1 knockdown inducedIL6expression in MCF7 cells. Chromatin immunoprecipitation assays revealed that FOXA1 bound to the promoter region ofIL6and repressed recruitment of the NF-κB complex to this region. TAM-R cells were found to have high mammosphere-forming activity, characteristics of cancer stem cells, and this activity was suppressed by NF-κB and IL6 signaling inhibitors. Taken together, these results suggest that FOXA1 suppresses expression ofIL6through inhibition of NF-κB recruitment to theIL6promoter in an ERα-independent manner and that reduction in FOXA1 expression inducesIL6expression and contributes to cancer stem cell-like properties in TAM-R cells.
authors.affiliation: Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675. Electronic address: yamaguchinoritaka@chiba-u.jp.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: Department of Biochemistry and Molecular Biology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Nakayama
authors.affiliation: Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D020218:Response Elements; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D009363:Neoplasm Proteins; D013629:Tamoxifen
keywords: NF-kappa B (NF-KB); breast cancer; cancer stem cells; estrogen receptor; interleukin 6 (IL-6)