Abstract
Trastuzumab (Herceptin) has been widely used in breast cancer treatment. However, the majority of cancers that initially respond to trastuzumab begin to progress again within 1 year. Despite the high resistance rate, the molecular mechanisms underlying this desease are not well understood. In the present study, microRNA (miRNA‑542‑3p modulated trastuzumab resistance in SKBR3 and MCF7/Her2 breast cancer cell lines. Trastuzumab induced miRNA‑542‑3p expression in SKBR3 and MCF7/Her2 cells. Furthermore, knockdown of miRNA‑542‑3p in the two cell lines resulted in decreased drug sensitivity to trastuzumab and cell apoptosis. The blockage of G1/S checkpoint by trastuzumab was rescued as well. miRNA‑542‑3p knockdown also activated the phosphatidylinositol 3‑kinase (PI3K)‑Akt pathway, while LY294002 reversed the effect of miRNA‑542‑3p knockdown. In summary, the results suggested that miRNA‑542‑3p downregulation may contribute to the trastuzumab resistance in breast cancer via, at least in part, the PI3K‑akt pathway. Our findings provide new molecular mechanisms in trastuzumab resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antibodies, Monoclonal, Humanized / pharmacology*
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Antineoplastic Agents / pharmacology*
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Apoptosis / genetics
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Cell Proliferation / genetics
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Chromones / pharmacology
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Down-Regulation
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Drug Resistance, Neoplasm / genetics*
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Enzyme Activation / genetics
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Enzyme Inhibitors / pharmacology
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Female
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Forkhead Box Protein O1
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Forkhead Transcription Factors / biosynthesis
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics
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Gene Knockdown Techniques
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Humans
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MCF-7 Cells
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MicroRNAs / biosynthesis
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MicroRNAs / genetics*
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Morpholines / pharmacology
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Oligonucleotides, Antisense / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, ErbB-2 / antagonists & inhibitors
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S Phase Cell Cycle Checkpoints / drug effects
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S Phase Cell Cycle Checkpoints / genetics
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Trastuzumab
Substances
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Chromones
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Enzyme Inhibitors
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FOXO1 protein, human
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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MIRN542 microRNA, human
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MicroRNAs
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Morpholines
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Oligonucleotides, Antisense
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Phosphoinositide-3 Kinase Inhibitors
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2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
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Receptor, ErbB-2
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Proto-Oncogene Proteins c-akt
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Trastuzumab