Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer

Oncotarget. 2016 May 10;7(19):27778-86. 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.

Keywords: drug resistance; lapatinib; lncRNA GAS5; mTOR; trastuzumab.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / genetics
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / genetics
  • Down-Regulation
  • Drug Resistance, Neoplasm / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic / genetics*
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • Lapatinib
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • MicroRNAs / metabolism
  • Microarray Analysis
  • PTEN Phosphohydrolase / genetics
  • Quinazolines / pharmacology
  • RNA, Long Noncoding / genetics
  • RNA, Long Noncoding / metabolism*
  • RNA, Small Interfering
  • Receptor, ErbB-2 / metabolism
  • Signal Transduction
  • TOR Serine-Threonine Kinases / metabolism
  • Trastuzumab / pharmacology*
  • Trastuzumab / therapeutic use
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Biomarkers, Tumor
  • GAS5 long non-coding RNA, human
  • MIRN21 microRNA, human
  • MicroRNAs
  • Quinazolines
  • RNA, Long Noncoding
  • RNA, Small Interfering
  • Lapatinib
  • MTOR protein, human
  • ERBB2 protein, human
  • Receptor, ErbB-2
  • TOR Serine-Threonine Kinases
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • Trastuzumab