Abstract
Drug resistance remains a major problem in the treatment of conventional chemotherapeutic agents in breast cancers. Owing to heterogeneity and complexity of chemoresistance mechanisms, most efforts that focus on a single pathway were unsuccessful, and exploring novel personalized therapeutics becomes urgent. By a system approach, we identified that microRNA-27b-3p (miR-27b), a miRNA deleted in breast cancer tissues and cell lines, has a master role in sensitizing breast cancer cells to a broad spectrum of anticancer drugs in vitro and in vivo. Mechanistic analysis indicated that miR-27b enhanced responses to PTX by directly targeting CBLB and GRB2 to inactivate both PI3K/Akt and MAPK/Erk signaling pathways. Further, miR-27b was identified as a promising molecular biomarker in chemoresistance, clinicopathological features, and prognosis for breast cancer patients. In conclusion, we propose that combinational use of miR-27b and chemotherapeutic agents might be a promising therapeutic strategy to increase long-term drug responses in breast cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / biosynthesis
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Adaptor Proteins, Signal Transducing / genetics*
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Animals
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Antineoplastic Agents, Phytogenic / pharmacology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Down-Regulation
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Drug Resistance, Multiple
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Drug Resistance, Neoplasm
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Female
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GRB2 Adaptor Protein / biosynthesis
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GRB2 Adaptor Protein / genetics*
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Humans
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MAP Kinase Signaling System / drug effects
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Mice
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Mice, Nude
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MicroRNAs / antagonists & inhibitors
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Paclitaxel / pharmacology
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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 / antagonists & inhibitors
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-cbl / biosynthesis
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Proto-Oncogene Proteins c-cbl / genetics*
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents, Phytogenic
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GRB2 Adaptor Protein
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GRB2 protein, human
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MIRN27 microRNA, human
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MicroRNAs
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Phosphoinositide-3 Kinase Inhibitors
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CBLB protein, human
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Proto-Oncogene Proteins c-cbl
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Proto-Oncogene Proteins c-akt
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Paclitaxel