title: Transcriptional repression of HER2 by ANO1 Cl-channel inhibition in human breast cancer cells with resistance to trastuzumab.
abstract: The Ca2+-activated Cl-channel ANO1 contributes to tumorigenesis and metastasis in several carcinomas including breast cancer (BCA). Cl-channels have recently been attracting attention as 'transcriptional modulators'. Human epidermal growth factor receptor 2 (HER2) is overexpressed in approximately 30% of patients with BCA, and anti-HER2 monoclonal antibodies such as trastuzumab have emerged as a treatment for metastatic BCA. Among the seven human BCA cell lines examined in the present study, MDA-MB-453 and YMB-1 cells were HER2-positive; however, YMB-1 cell viability showed resistance to trastuzumab. Whole-cell patch-clamp configurations indicated that ANO1 was the main Cl-conductance in YMB-1 cells, and the pharmacological and siRNA-mediated inhibition of ANO1 significantly prevented HER2 transcription in YMB-1 cells. The expression levels of insulin-like growth factor-binding protein 5 (IGFBP5), which is a risk factor for BCA recurrence and metastasis, was not affected by the inhibition of ANO1 in YMB-1 cells. These results suggest that ANO1 Cl-channels may function as a transcriptional regulator of HER2, and ANO1 inhibitors have potential in the treatment of BCA patients with resistance to HER2-targeted therapy.
authors.affiliation: Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kito
authors.affiliation: Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Niwa
authors.affiliation: Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto 603-8334, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya 464-8650, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
authors.affiliation: Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan. Electronic address: sohya@mb.kyoto-phu.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
mesh_terms: D000075369:Anoctamin-1; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects*; D000068878:Trastuzumab / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000075369:Anoctamin-1; D000970:Antineoplastic Agents; D018118:Chloride Channels; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C476213:ANO1 protein, human; C508053:ERBB2 protein, human
keywords: ANO1; Breast cancer; Ca(2+)-activated Cl(−) channel; HER2; IGFBP5; Resistance to HER2-targeted therapy