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

Myeongjin Jeon,Daeun You,Soo Youn Bae,Jeong Eon Lee,Sangmin Kim,Seok Won Kim,Seok Jin Nam,Hyeon Ho Kim

doi:10.18632/oncotarget.10843

Myeongjin Jeon, Daeun You + Show 6 more

Open Access

https://doi.org/10.18632/oncotarget.10843

Copy DOI

Journal: Oncotarget	Publication Date: Jul 26, 2016
Citations: 33	License type: cc-by

Affiliation: Samsung Medical Center, Sungkyunkwan University

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.

Highlights

The HER2 gene is amplified in approximately 25–30% of primary breast tumors and is one of the most significant genetic changes in breast cancer [1]
These results demonstrated that induction of ACTA2 by EGFR and HER2 dimerization was regulated through a JAK2/signal transducer and activator of transcription 1 (STAT1) signaling pathway, and aberrant ACTA2 expression accelerated the invasiveness and metastasis of breast cancer cells
By analyzing the public dataset, we found that ACTA2 and STAT1 expression were relatively higher in HER2-positive than in HER2-negative breast cancers (Figure 1C)

Summary

Introduction

The HER2 gene is amplified in approximately 25–30% of primary breast tumors and is one of the most significant genetic changes in breast cancer [1]. Breast cancer patients with HER2 overexpression show aggressive clinical course, including poor disease-free and overall survival, chemo-resistance, and shorter time to relapse [4, 5]. Despite the clinical benefits of these HER2-targeted therapies, the response rate for trastuzumab as a single agent remains less than satisfactory at around 35% and the vast majority of tumors that respond to trastuzumab develop resistance within 1 to 2 years of treatment [6]. Its activation is achieved through dimerization with other ligand-bound HER family receptors such as EGFR [7, 8]. EGFR and HER2 are frequently overexpressed in breast cancer, and their dimerization is associated with more aggressive clinical behavior [7, 8]. The heterodimerization of EGFR with HER2 induces a more potent EGFR activation than www.impactjournals.com/oncotarget

Objectives

Methods

Results

Conclusion