title: Up-regulation of miR-21 mediates resistance to trastuzumab therapy for breast cancer.
abstract: Trastuzumab resistance emerges to be a major issue in anti-human epidermal growth factor receptor 2 (HER2) therapy for breast cancers. Here, we demonstrated that miR-21 expression was up-regulated and its function was elevated in HER2(+) BT474, SKBR3, and MDA-MB-453 breast cancer cells that are induced to acquire trastuzumab resistance by long-term exposure to the antibody, whereas protein expression of the PTEN gene, a miR-21 target, was reduced. Blocking the action of miR-21 with antisense oligonucleotides re-sensitized the resistant cells to the therapeutic activities of trastuzumab by inducing growth arrest, proliferation inhibition, and G(1)-S cell cycle checking in the presence of the antibody. Ectopic expression of miR-21 in HER2(+) breast cancer cells confers resistance to trastuzumab. Rescuing PTEN expression with a p3XFLAG-PTEN-mut construct with deleted miR-21 targeting sequence at its 3' UTR restored the growth inhibition of trastuzumab in the resistant cells by inducing PTEN activation and AKT inhibition. In vivo, administering miR-21 antisense oligonucleotides restored trastuzumab sensitivity in the resistant breast cancer xenografts by inducing PTEN expression, whereas injection of miR-21 mimics conferred trastuzumab resistant in the sensitive breast tumors via PTEN silence. Up-regulatin of miR-21 in tumor biopsies obtained from patients receiving pre-operative trastuzumab therapy was associated with poor trastuzumab response. Therefore, miR-21 overexpression contributes to trastuzumab resistance in HER2(+) breast cancers and antagonizing miR-21 demonstrates therapeutic potential by sensitizing the malignancy to anti-HER2 treatment.
authors.affiliation: Breast Tumor Center, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Gong
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yao
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.forename: Bodu
authors.initials: B
authors.lastname: Liu
authors.forename: Wei
authors.initials: W
authors.lastname: Wu
authors.forename: Jianing
authors.initials: J
authors.lastname: Chen
authors.forename: Fengxi
authors.initials: F
authors.lastname: Su
authors.forename: Herui
authors.initials: H
authors.lastname: Yao
authors.forename: Erwei
authors.initials: E
authors.lastname: Song
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D016193:G1 Phase / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis* / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000187:drug effects / Q000235:genetics; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D035683:MicroRNAs; D020319:Oligodeoxyribonucleotides, Antisense; D051059:PTEN Phosphohydrolase; D012334:RNA, Neoplasm; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C524940:MIRN21 microRNA, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human