Department of Molecular Toxicology, Faculty of Pharmaceutical Sciences, Toho University, Miyama 2-2-1, Funabashi, Chiba 274-8510, Japan.
Department of Clinical-Laboratory and Experimental-Research Medicine, Toho University Sakura Medical Center, Shimoshizu 564-1, Sakura, Chiba 285-8741, Japan; Department of Surgical Pathology, Toho University Sakura Medical Center, Shimoshizu 564-1, Sakura, Chiba 285-8741, Japan.
Exp Cell Res. 2018 May 1;366(1):34-40. doi: 10.1016/j.yexcr.2018.02.033. Epub 2018 Mar 1.
HER2 overexpression accounts for approximately 15-20% of all breast cancers. We have shown that HER2 overexpression leads to elevated expression of the aryl hydrocarbon receptor (AhR) in breast cancer cells. In this study, firstly, we showed that AhR expression was up-regulated by treatment with the HER3 ligand heregulin (HRG) in HER2-overexpressing breast cancer cell lines. Induction of AhR was mediated by transcriptional activation of the region of AhR promoter corresponding to - 190 to - 100 bp. In addition, HRG treatment elicited nuclear translocation of AhR. To investigate the role of AhR in HRG-HER2/HER3 signaling in HER2-overexpressing cells, we established AhR knockout (KO) HER2-overexpressing cells to perform wound-healing assays. HRG-induced cell migration was markedly attenuated by AhR KO. HRG-induced cell migration was associated with increased expression of the inflammatory cytokines interleukin (IL)-6 and IL-8 in wild type cells, but not in AhR KO cells. These results elucidate that AhR is an important factor for the malignancy in HER2 overexpressing breast cancers.
HER2 过表达约占所有乳腺癌的 15-20%。我们已经表明，HER2 过表达导致乳腺癌细胞中芳香烃受体 (AhR) 的表达升高。在这项研究中，首先，我们表明，HER2 过表达的乳腺癌细胞系中，HER3 配体 HRG 的处理上调了 AhR 的表达。AhR 的诱导是通过 AhR 启动子区域的转录激活介导的，该区域对应于 -190 到 -100 bp。此外，HRG 处理引发了 AhR 的核转位。为了研究 AhR 在 HRG-HER2/HER3 信号通路中的作用，我们建立了 AhR 敲除 (KO) 的 HER2 过表达细胞，以进行划痕愈合测定。AhR KO 显著减弱了 HRG 诱导的细胞迁移。HRG 诱导的细胞迁移与野生型细胞中炎症细胞因子白细胞介素 (IL)-6 和 IL-8 的表达增加有关，但在 AhR KO 细胞中没有。这些结果表明，AhR 是 HER2 过表达乳腺癌恶性程度的重要因素。
