Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer

// Wentong Li 1 , Limin Zhai 1 , Hui Wang 2 , Chuanliang Liu 3 , Jinbao Zhang 4 , Weijuan Chen 5 , Qun Wei 5 1 Department of Pathology, Weifang Medical University, Weifang, Shandong Province, 261053, P.R. China 2 Department of Oncology, People’s Hospital of Shouguang City, Shandong Province, 262700, P.R. China 3 Department of Health Care, Weifang People’s Hospital, Weifang, Shandong Province, 261053, P.R. China 4 Department of Molecular Genetics, Weifang Medical University, Weifang, Shandong Province, 261053, P.R. China 5 Department of Pathology, People’s Hospital of Shouguang City, Shandong Province, 262700, P.R. China Correspondence to: Wentong Li, e-mail: liwentong11@163.com Keywords: trastuzumab, lapatinib, drug resistance, lncRNA GAS5, mTOR Received: January 28, 2016 Accepted: March 16, 2016 Published: March 28, 2016 ABSTRACT Therapeutic resistance to trastuzumab caused by dysregulation of long noncoding RNAs (lncRNAs) is a major obstacle to clinical management of HER2-positive breast cancer. To investigate which lncRNAs contribute to trastuzumab resistance, we screened a microarray of lncRNAs involved in the malignant phenotype of trastuzumab-resistant SKBR-3/Tr cells. Expression of the lncRNA GAS5 was decreased in SKBR-3/Tr cells and in breast cancer tissue from trastuzumab-treated patients. Inhibition of GAS5 promoted SKBR-3 cell proliferation, and GAS5 knockdown partially reversed lapatinib-induced inhibition of SKBR-3/Tr cell proliferation. GAS5 suppresses cancer proliferation by acting as a molecular sponge for miR-21, leading to the de-repression of phosphatase and tensin homologs (PTEN), the endogenous target of miR-21. Moreover, mTOR activation associated with reduced GAS5 expression was required to suppress PTEN. This work identifies GAS5 as a novel prognostic marker and candidate drug target for HER2-positive breast cancer.