Abstract
The CSF-1 receptor (CSF-1R) is expressed in >50% of human breast cancers. To investigate the consequence of CSF-1R expression, hormone-dependent human breast cancer cell lines, MCF-7 and T-47D, were transfected with CSF-1R. Unexpectedly, CSF-1 substantially inhibited estradiol (E2) and insulin-dependent proliferation of MCF-7 transfectants (MCF-7fms) and prevented cyclin E/cdk2 and cyclin A/cdk2 activation, consistent with a G1 arrest. In contrast, CSF-1 increased DNA synthesis in T-47D transfectants (T-47Dfms) alone and with E2 or insulin. In response to CSF-1, there was a marked and sustained upregulation of the cyclin-dependent kinase inhibitor, p21Waf1/Cip1, in MCF-7fms but not T-47Dfms. CSF-1 also markedly upregulated cyclin D1 in MCF-7fms. The coordinate increase in cyclin D1 and p21 had the effect of decreasing the specific but not absolute activity of cyclin D1/cdk4. p53 was not involved since CSF-1 induction of p21 was unaffected by dominant-negative p53 expression. ERK activation by CSF-1 was robust and sustained in MCF-7fms and to a much lesser extent in T-47Dfms. Using pharmacological and transient transfection approaches, we showed that ERK activation was necessary and sufficient for p21 induction in MCF-7fms. Moreover, activated MEK inhibited E2-stimulated cdk2 activity. Our findings indicate that the consequence of CSF-1R-mediated signals in human breast cancer cells is dependent on the genetic background of the particular tumor.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism*
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Breast Neoplasms / pathology*
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CDC2-CDC28 Kinases*
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Cell Division / drug effects
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Cell Division / physiology
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Cyclin D1 / drug effects
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Cyclin D1 / genetics
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Cyclin D1 / metabolism
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Cyclin E / drug effects
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Cyclin E / metabolism
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclin-Dependent Kinases / drug effects
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Cyclin-Dependent Kinases / metabolism
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Cyclins / drug effects
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Cyclins / genetics
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Cyclins / metabolism
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Enzyme Inhibitors / pharmacology
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Estradiol / metabolism
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Estradiol / pharmacology
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Female
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Flavonoids / pharmacology
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Humans
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Insulin / pharmacology
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MAP Kinase Kinase Kinase 1*
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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MAP Kinase Kinase Kinases / metabolism
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Macrophage Colony-Stimulating Factor / metabolism*
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Macrophage Colony-Stimulating Factor / pharmacology
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Mitogen-Activated Protein Kinase Kinases / drug effects
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Phosphorylation / drug effects
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Protein Serine-Threonine Kinases / drug effects
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins*
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Receptor, Macrophage Colony-Stimulating Factor / genetics
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Receptors, Estrogen / metabolism*
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Resting Phase, Cell Cycle / drug effects
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Retinoblastoma Protein / drug effects
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Retinoblastoma Protein / metabolism
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S Phase / drug effects
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Tumor Cells, Cultured
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Tumor Suppressor Protein p53 / metabolism*
Substances
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CDKN1A protein, human
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Cyclin E
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Cyclin-Dependent Kinase Inhibitor p21
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Cyclins
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Enzyme Inhibitors
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Flavonoids
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Insulin
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Proto-Oncogene Proteins
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Receptors, Estrogen
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Retinoblastoma Protein
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Tumor Suppressor Protein p53
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Cyclin D1
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Estradiol
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Macrophage Colony-Stimulating Factor
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Receptor, Macrophage Colony-Stimulating Factor
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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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CDK4 protein, human
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Cyclin-Dependent Kinase 2
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Cyclin-Dependent Kinase 4
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Cyclin-Dependent Kinases
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MAP Kinase Kinase Kinase 1
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MAP Kinase Kinase Kinases
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MAP3K1 protein, human
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Mitogen-Activated Protein Kinase Kinases
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2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one