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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
21
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pubmed:dateCreated |
2011-5-23
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal,
http://linkedlifedata.com/resource/pubmed/chemical/Antibodies, Monoclonal, Humanized,
http://linkedlifedata.com/resource/pubmed/chemical/Antineoplastic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/HER2 protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/MIRN21 microRNA, human,
http://linkedlifedata.com/resource/pubmed/chemical/MicroRNAs,
http://linkedlifedata.com/resource/pubmed/chemical/Oligodeoxyribonucleotides, Antisense,
http://linkedlifedata.com/resource/pubmed/chemical/PTEN Phosphohydrolase,
http://linkedlifedata.com/resource/pubmed/chemical/PTEN protein, human,
http://linkedlifedata.com/resource/pubmed/chemical/RNA, Neoplasm,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, erbB-2,
http://linkedlifedata.com/resource/pubmed/chemical/trastuzumab
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
1083-351X
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pubmed:author |
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pubmed:issnType |
Electronic
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pubmed:day |
27
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pubmed:volume |
286
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
19127-37
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pubmed:dateRevised |
2011-11-17
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pubmed:meshHeading |
pubmed-meshheading:21471222-Antibodies, Monoclonal,
pubmed-meshheading:21471222-Antibodies, Monoclonal, Humanized,
pubmed-meshheading:21471222-Antineoplastic Agents,
pubmed-meshheading:21471222-Breast Neoplasms,
pubmed-meshheading:21471222-Carcinoma, Ductal, Breast,
pubmed-meshheading:21471222-Drug Resistance, Neoplasm,
pubmed-meshheading:21471222-Female,
pubmed-meshheading:21471222-G1 Phase,
pubmed-meshheading:21471222-Gene Expression Regulation, Enzymologic,
pubmed-meshheading:21471222-Gene Expression Regulation, Neoplastic,
pubmed-meshheading:21471222-Gene Silencing,
pubmed-meshheading:21471222-Humans,
pubmed-meshheading:21471222-MicroRNAs,
pubmed-meshheading:21471222-Oligodeoxyribonucleotides, Antisense,
pubmed-meshheading:21471222-PTEN Phosphohydrolase,
pubmed-meshheading:21471222-RNA, Neoplasm,
pubmed-meshheading:21471222-Receptor, erbB-2,
pubmed-meshheading:21471222-S Phase,
pubmed-meshheading:21471222-Tumor Cells, Cultured,
pubmed-meshheading:21471222-Up-Regulation
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pubmed:year |
2011
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pubmed:articleTitle |
Up-regulation of miR-21 mediates resistance to trastuzumab therapy for breast cancer.
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pubmed:affiliation |
Breast Tumor Center, Sun-Yat-Sen Memorial Hospital, Sun-Yat-Sen University, Guangzhou 510120, China.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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