Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer.

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

doi:10.18632/oncotarget.8413

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.

Highlights

HER2 overexpression and amplification are detected in 15%–20% of breast cancers and correlate with poor prognosis and short survival [1, 2]
To investigate which long noncoding RNAs (lncRNAs) contribute to trastuzumab resistance, we screened a microarray of lncRNAs involved in the malignant phenotype of trastuzumab-resistant SKBR-3/Tr cells
GAS5 is downregulated in SKBR-3/Tr cells and trastuzumab-treated breast cancer tissues

Summary

Introduction

HER2 overexpression and amplification are detected in 15%–20% of breast cancers and correlate with poor prognosis and short survival [1, 2]. Anti-human HER2 antibody therapy using trastuzumab is used to treat HER2-positive, early-stage, and metastatic breast cancers but less than 35% of patients initially respond [3, 4]. The remainder are inherently resistant or acquire resistance during disease progression. Trastuzumab resistance remains an obstacle for treatment of these patients [5,6,7]. A recently discovered mechanism of trastuzumab resistance is the dysregulation of long noncoding RNAs (lncRNAs). Previous studies showed that lnc-ATB promotes trastuzumab resistance and invasion–metastasis cascade in breast cancer by competitively binding to miR200c, thereby upregulating ZEB1 [8]

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