Human epidermal growth factor receptor 2 inhibits activating transcription factor 7 to promote breast cancer cell migration by activating histone lysine demethylase 1.

Abstract

Receptor tyrosine-protein kinase erbB-2 (human epidermal growth factor receptor 2 [HER2])-based therapies can improve the prognosis of HER2-positive breast cancer (BRCA) patients; however, HER2-positive patients with distal metastasis do not gain significant clinical benefit from molecular targeted therapy. A database analysis, immunohistochemistry, and quantitative real-time polymerase chain reaction were used to evaluate the expression of activating transcription factor 7 (ATF7) and its clinical value. A transwell chamber assay was used to assess migration and cell signaling was assessed by immunoblotting. ATF7 was expressed at a low level in HER2-enriched BRCA specimens compared with normal or HER2-negative specimens, which was corroborated in HER2-positive tissue chips and cultured cells. ATF7 gradually decreased with increased tumor stage and low ATF7 was associated with poor prognosis in HER2-positive BRCA patients. ATF7-upregulation inhibited, whereas ATF7-knockdown promoted migration, activity of matrix metalloproteinase 9 (MMP9), MMP2, and uridylyl phosphate adenosine and plasminogen activator inhibitor-1 (PAI-1) expression in HER2-positive cells. HER2 overexpression markedly reduced ATF7 expression in MCF-10A mammary epithelial cells, along with decreased E-cadherin, and increased N-cadherin and migration, which were abrogated by exogenous ATF7 transfection. Mechanistically, HER2 upregulation mediated the decline of ATF7 and activated histone lysine demethylase 1 (LSD1), followed by elevation of histone H3K9 dimethylation (H3K9me2) and H3K4me2. However, the enhanced effects on LSD1 and H3K9me2, excluding H3K4me2, were abrogated by exogenous ATF7. ATF7 was negatively associated with KDM1A (encoding LSD1 protein) expression. ATF7 may be a useful diagnostic and prognostic marker for metastatic HER2-positive BRCA. The ATF7/LSD1/H3K9me2 axis may be responsible for metastasis in HER2-positive cells.