Abstract
Previously we reported that neu differentiation factor (NDF)/heregulin (HRG) elevates tyrosine phosphorylation of its receptors erbB-3, erbB-4, and erbB-2 (through heterodimer formation). We also showed that both NDF/HRG and antibodies to erbB-2 can arrest growth and induce differentiation in breast cancer cells. In this study, we report on the mechanism of NDF/HRG-induced cellular effects. We show that NDF/HRG and antibodies to erbB-2 receptors up-regulate expression of p53 by stabilizing the protein. This is accompanied by up-regulation of the p53 inducible gene, p21CIP1/WAF1, in a variety of cell lines: MCF7 and their derivatives (MCF7/HER2, MN1 and MCF-7-puro), ZR75T and LnCap cells. The induction of p21 is further enhanced when cells are treated with both NDF/HRG and DNA-damaging chemotherapeutic agents (i.e. doxorubicin). The NDF/HRG mediated induction of p21 is dependent on wildtype p53, as it fails to occur in cells expressing dominant negative p53 (MDD2). Furthermore, p21 induction is capable of inactivating cdk2 complexes as measured by Histone H1 phosphorylation assays. Finally, we show that in primary cultures of breast and other cancers, p21 is significantly induced in response to NDF/HRG treatment. Collectively, these observations suggest that the mechanism of breast cancer cell growth inhibition and differentiation via erbB receptors activation is through a p53-mediated pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Antibodies, Monoclonal / pharmacology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology
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CDC2-CDC28 Kinases*
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / antagonists & inhibitors
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Cyclins / biosynthesis
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Cyclins / drug effects
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Cyclins / genetics*
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Doxorubicin / pharmacology
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Endometrial Neoplasms / drug therapy
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Endometrial Neoplasms / genetics
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Endometrial Neoplasms / pathology
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Enzyme Inhibitors / pharmacology
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ErbB Receptors / biosynthesis
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ErbB Receptors / drug effects
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ErbB Receptors / genetics
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Female
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Gene Expression Regulation, Neoplastic
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Genes, p53
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Glycoproteins / genetics
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Glycoproteins / pharmacology*
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Humans
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Male
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Neuregulins
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Prostatic Neoplasms / drug therapy
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Prostatic Neoplasms / genetics*
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Prostatic Neoplasms / pathology
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / drug effects
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Proto-Oncogene Proteins / genetics
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Receptor, ErbB-2 / drug effects
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Receptor, ErbB-2 / genetics
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Receptor, ErbB-2 / immunology
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Receptor, ErbB-3
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Receptor, ErbB-4
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / drug effects
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Up-Regulation
Substances
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Antibodies, Monoclonal
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CDKN1A protein, human
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Enzyme Inhibitors
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Glycoproteins
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Neuregulins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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Doxorubicin
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ERBB4 protein, human
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ErbB Receptors
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Receptor, ErbB-2
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Receptor, ErbB-3
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Receptor, ErbB-4
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Protein Serine-Threonine Kinases
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CDC2-CDC28 Kinases
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CDK2 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinases