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.
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Authors | A W Lee, S Nambirajan, J G Moffat |
Journal | Oncogene
(Oncogene)
Vol. 18
Issue 52
Pg. 7477-94
(Dec 09 1999)
ISSN: 0950-9232 [Print] England |
PMID | 10602507
(Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- CDKN1A protein, human
- Cyclin E
- Cyclin-Dependent Kinase Inhibitor p21
- Cyclins
- Enzyme Inhibitors
- Flavonoids
- Insulin
- Proto-Oncogene Proteins
- Receptors, Estrogen
- Retinoblastoma Protein
- Tumor Suppressor Protein p53
- Cyclin D1
- Estradiol
- Macrophage Colony-Stimulating Factor
- Receptor, Macrophage Colony-Stimulating Factor
- Protein Serine-Threonine Kinases
- CDC2-CDC28 Kinases
- CDK2 protein, human
- CDK4 protein, human
- Cyclin-Dependent Kinase 2
- Cyclin-Dependent Kinase 4
- Cyclin-Dependent Kinases
- MAP Kinase Kinase Kinase 1
- MAP Kinase Kinase Kinases
- MAP3K1 protein, human
- Mitogen-Activated Protein Kinase Kinases
- 2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
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Topics |
- Breast Neoplasms
(drug therapy, metabolism, pathology)
- CDC2-CDC28 Kinases
- Cell Division
(drug effects, physiology)
- Cyclin D1
(drug effects, genetics, metabolism)
- Cyclin E
(drug effects, metabolism)
- Cyclin-Dependent Kinase 2
- Cyclin-Dependent Kinase 4
- Cyclin-Dependent Kinase Inhibitor p21
- Cyclin-Dependent Kinases
(drug effects, metabolism)
- Cyclins
(drug effects, genetics, metabolism)
- Enzyme Inhibitors
(pharmacology)
- Estradiol
(metabolism, pharmacology)
- Female
- Flavonoids
(pharmacology)
- Humans
- Insulin
(pharmacology)
- MAP Kinase Kinase Kinase 1
- MAP Kinase Kinase Kinases
(antagonists & inhibitors, metabolism)
- Macrophage Colony-Stimulating Factor
(metabolism, pharmacology)
- Mitogen-Activated Protein Kinase Kinases
(drug effects, metabolism)
- Phosphorylation
(drug effects)
- Protein Serine-Threonine Kinases
(drug effects, metabolism)
- Proto-Oncogene Proteins
- Receptor, Macrophage Colony-Stimulating Factor
(genetics, metabolism)
- Receptors, Estrogen
(metabolism)
- Resting Phase, Cell Cycle
(drug effects)
- Retinoblastoma Protein
(drug effects, metabolism)
- S Phase
(drug effects)
- Tumor Cells, Cultured
- Tumor Suppressor Protein p53
(metabolism)
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