Abstract
Reversion of the malignant phenotype of erbB2-transformed cells can be driven by anti-erbB2/neu monoclonal antibodies (mAbs), which disrupt the receptor's kinase activity. We examined the biologic effects of IFN-γ alone or after anti-erbB2/neu mAb treatment of erbB2-positive cells. IFN-γ had no effect on its own. Treatment of the tumors with anti-erbB2/neu mAbs followed by IFN-γ led to dramatic inhibition of tumor growth in vitro and in vivo with minimal mAb dosing. Sequential therapy enhanced the effects of chemotherapy. Moreover, IFN-γ with mAb treatment of mice with IFNγR knockdown tumors did not demonstrate marked synergistic eradication effects, indicating an unexpected role of IFN-γ on the tumor itself. Additionally, mAb and IFN-γ treatment also induced immune host responses that enhanced tumor eradication. Biochemical analyses identified loss of Snail expression in tumor cells, reflecting diminution of tumor-stem-cell-like properties as a consequence of altered activity of GSK3-β and KLF molecules.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antineoplastic Agents / 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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Cell Proliferation / drug effects
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Female
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Gene Expression Regulation, Neoplastic*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Interferon gamma Receptor
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Interferon-gamma / pharmacology*
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Kruppel-Like Transcription Factors / genetics
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Mice, Inbred BALB C
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Neoplasm Transplantation
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Phenotype
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / metabolism
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Receptors, Interferon / deficiency
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Receptors, Interferon / genetics
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Signal Transduction
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Snail Family Transcription Factors
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Trastuzumab / pharmacology*
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Tumor Burden / drug effects
Substances
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Antineoplastic Agents
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Kruppel-Like Transcription Factors
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Receptors, Interferon
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Snail Family Transcription Factors
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Transcription Factors
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erythroid Kruppel-like factor
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Interferon-gamma
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ERBB2 protein, human
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Receptor, ErbB-2
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3
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Trastuzumab