Oncotarget

Research Papers:

Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer

Wentong Li _, Limin Zhai, Hui Wang, Chuanliang Liu, Jinbao Zhang, Weijuan Chen and Qun Wei

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Oncotarget. 2016; 7:27778-27786. https://doi.org/10.18632/oncotarget.8413

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Abstract

Wentong Li1, Limin Zhai1, Hui Wang2, Chuanliang Liu3, Jinbao Zhang4, Weijuan Chen5, Qun Wei5

1Department of Pathology, Weifang Medical University, Weifang, Shandong Province, 261053, P.R. China

2Department of Oncology, People’s Hospital of Shouguang City, Shandong Province, 262700, P.R. China

3Department of Health Care, Weifang People’s Hospital, Weifang, Shandong Province, 261053, P.R. China

4Department of Molecular Genetics, Weifang Medical University, Weifang, Shandong Province, 261053, P.R. China

5Department of Pathology, People’s Hospital of Shouguang City, Shandong Province, 262700, P.R. China

Correspondence to:

Wentong Li, e-mail: [email protected]

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.


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