Abstract
Resistance to Herceptin represents a significant challenge for successful treatment of HER2-positive breast cancer. Here, we show that in Herceptin-sensitive cells, FOXO3a regulates specific miRNAs to control IGF2 and IRS1 expression, retaining basic IGF2/IGF-1R/IRS1 signaling. The basic activity maintains expression of PPP3CB, a subunit of the serine/threonine-protein phosphatase 2B, to restrict FOXO3a phosphorylation (p-FOXO3a), inducing IGF2- and IRS1-targeting miRNAs. However, in Herceptin-resistant cells, p-FOXO3a levels are elevated due to transcriptional suppression of PPP3CB, disrupting the negative feedback inhibition loop formed by FOXO3a and the miRNAs, thereby upregulating IGF2 and IRS1. Moreover, we detect significantly increased IGF2 in blood and IRS1 in the tumors of breast cancer patients with poor response to Herceptin-containing regimens. Collectively, we demonstrate that the IGF2/IGF-1R/IRS1 signaling is aberrantly activated in Herceptin-resistant breast cancer via disruption of the FOXO3a-miRNA negative feedback inhibition. Such insights provide avenues to identify predictive biomarkers and effective strategies overcoming Herceptin resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents, Immunological / pharmacology
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Breast Neoplasms / genetics*
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Breast Neoplasms / metabolism
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Breast Neoplasms / mortality
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Breast Neoplasms / pathology
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Calcineurin / genetics
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Calcineurin / metabolism
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Cell Line, Tumor
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Drug Resistance, Neoplasm / genetics
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Feedback, Physiological
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Female
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Forkhead Box Protein O3 / genetics*
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Forkhead Box Protein O3 / metabolism
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Gene Expression Regulation, Neoplastic
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Humans
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Insulin Receptor Substrate Proteins / genetics*
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Insulin Receptor Substrate Proteins / metabolism
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Insulin-Like Growth Factor II / genetics*
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Insulin-Like Growth Factor II / metabolism
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Mice
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Mice, Nude
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MicroRNAs / genetics*
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MicroRNAs / metabolism
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Phosphorylation
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Receptor, ErbB-2 / genetics*
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Receptor, ErbB-2 / metabolism
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Receptor, IGF Type 1 / genetics*
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Receptor, IGF Type 1 / metabolism
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Signal Transduction
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Survival Analysis
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Trastuzumab / pharmacology
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Tumor Burden / drug effects
Substances
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Antineoplastic Agents, Immunological
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FOXO3 protein, human
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Forkhead Box Protein O3
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IGF1R protein, human
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IGF2 protein, human
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IRS1 protein, human
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Insulin Receptor Substrate Proteins
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MIRN128 microRNA, human
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MIRN30b microRNA, human
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MicroRNAs
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Insulin-Like Growth Factor II
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ERBB2 protein, human
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Receptor, ErbB-2
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Receptor, IGF Type 1
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Calcineurin
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PPP3CB protein, human
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Trastuzumab