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.

Keywords: ANO1; Breast cancer; Ca(2+)-activated Cl(−) channel; HER2; IGFBP5; Resistance to HER2-targeted therapy.