title: Downregulation of LncRNA GAS5 causes trastuzumab resistance in breast cancer.
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.
authors.affiliation: Department of Pathology, Weifang Medical University, Weifang, Shandong Province, 261053, P.R. China.
authors.forename: Wentong
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Pathology, Weifang Medical University, Weifang, Shandong Province, 261053, P.R. China.
authors.forename: Limin
authors.initials: L
authors.lastname: Zhai
authors.affiliation: Department of Oncology, People's Hospital of Shouguang City, Shandong Province, 262700, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Health Care, Weifang People's Hospital, Weifang, Shandong Province, 261053, P.R. China.
authors.forename: Chuanliang
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular Genetics, Weifang Medical University, Weifang, Shandong Province, 261053, P.R. China.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Pathology, People's Hospital of Shouguang City, Shandong Province, 262700, P.R. China.
authors.forename: Weijuan
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Pathology, People's Hospital of Shouguang City, Shandong Province, 262700, P.R. China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wei
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D055785:Gene Knockdown Techniques; D006801:Humans; D007150:Immunohistochemistry; D000077341:Lapatinib; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000378:metabolism; D046228:Microarray Analysis; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000068878:Trastuzumab / Q000494:pharmacology* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000077341:Lapatinib; D035683:MicroRNAs; D051059:PTEN Phosphohydrolase; D011799:Quinazolines; D062085:RNA, Long Noncoding; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; D000068878:Trastuzumab; C561567:GAS5 long non-coding RNA, human; C524940:MIRN21 microRNA, human; C546842:MTOR protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human
keywords: drug resistance; lapatinib; lncRNA GAS5; mTOR; trastuzumab