Lower Beclin 1 downregulates HER2 expression to enhance tamoxifen sensitivity and predicts a favorable outcome for ER positive breast cancer

Abstract

// Yu Gu 1, 2 , Tianxiang Chen 3 , Guangliang Li 4 , Cong Xu 2 , Zhenzhen Xu 2 , Jing Zhang 2 , Kuifeng He 2 , Linyan Zheng 2 , Zhonghai Guan 2 , Xinyun Su 2 , Jiang Cao 5 and Lisong Teng 2 1 Department of Radiation Oncology, Shanghai Cancer Hospital, Fudan University, Shanghai, China 2 Department of Surgical Oncology, The 1st Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China 3 Department of Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China 4 Department of Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang Province, China 5 Clinical Research Center, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China Correspondence to: Lisong Teng, email: lsteng@zju.edu.cn Keywords: breast cancer, tamoxifen resistance, prognosis, beclin 1, HER2 Received: September 16, 2015     Accepted: June 29, 2016     Published: August 04, 2016 ABSTRACT Tamoxifen(TAM) is one of the most effective endocrine treatment for estrogen receptor(ER)-positive breast cancer, however drug resistance greatly limits benefit of it. Our purpose is to uncover the role of Beclin 1 in tamoxifen resistance and prognosis of ER positive breast cancer. We established a tamoxifen resistant ER-positive breast cancer cell subline MCF-7R presenting with higher Beclin 1 and human epidermal growth factor receptor 2(HER2) levels than MCF-7. Silencing Beclin 1 decreased levels of HER2 and significantly promoted TAM sensitivity of MCF-7 and MCF-7R in vitro . Overexpression of HER2 could reverse TAM sensitivity, which was formerly increased in Beclin 1 downregulated cell. Beclin 1 level was not only positively correlated with level of HER2 but also negatively correlated with overall survival of ER-positive breast cancer patients. Using bioinformatic methods, Beclin 1 mRNA was found to be negatively correlated with overall survival in breast cancer patients receiving TAM treatment. This study indicated for the first time that lower HER2 expression by Beclin 1 downregulation contributes to alteration of tamoxifen sensitivity and low Beclin 1 predicts favorable outcome in ER-positive breast cancer.