Dimerization of EGFR and HER2 induces breast cancer cell motility through STAT1-dependent ACTA2 induction

Abstract

// Myeongjin Jeon 1, 2 , Daeun You 1, 2 , Soo Youn Bae 1 , Seok Won Kim 1 , Seok Jin Nam 1 , Hyeon Ho Kim 2 , Sangmin Kim 1 and Jeong Eon Lee 1, 2 1 Department of Surgery, Samsung Medical Center, Gangnam-gu, Seoul 06351, Korea 2 Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Gangnam-gu, Seoul 06351, Korea Correspondence to: Sangmin Kim, email: sangmin3005.kim@samsung.com Jeong Eon Lee, email: paojlus@hanmail.net Keywords: ACTA2, HER2, STAT1, invasion, metastasis Received: April 14, 2016      Accepted: July 10, 2016      Published: July 26, 2016 ABSTRACT The dimerization of EGFR and HER2 is associated with poor prognosis such as induction of tumor growth and cell invasion compared to when EGFR remains as a homodimer. However, the mechanism for events after dimerization in breast cancer models is not clear. We found that expressions of alpha-smooth muscle actin (ACTA2) and signal transducer and activator of transcription 1 (STAT1) significantly increased with transient or stable overexpression of HER2 in EGFR-positive breast cancer cells. ACTA2 and STAT1 expression was also increased in HER2-positive breast cancer patients. In contrast, ACTA2 expression was decreased by HER2 siRNA. Next, we investigated the co-relation between STAT1 and ACTA2 expression. Basal ACTA2 expression was significantly decreased by treatment with the STAT1 inhibitor fludarabine or the JAK2 inhibitor AG490. In contrast, ACTA2 expression was increased by STAT1 overexpression. Levels of ACTA2, STAT1, and HER2 were increased and relapse free survival was decreased in high-risk breast cancer patients. We also investigated the effect of ACTA2 on cell motility, which was suppressed by ACTA2 shRNA overexpression in MDA-MB231 HER2 and 4T1 mammary carcinoma cells. The number of lung metastatic nodules was significantly decreased in ACTA2 knockdown mice. Taken together, these results demonstrated that induction of ACTA2 by EGFR and HER2 dimerization was regulated through a JAK2/STAT1 signaling pathway, and aberrant ACTA2 expression accelerated the invasiveness and metastasis of breast cancer cells.