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CSF-1 activates MAPK-dependent and p53-independent pathways to induce growth arrest of hormone-dependent human breast cancer cells.

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.
AuthorsA W Lee, S Nambirajan, J G Moffat
JournalOncogene (Oncogene) Vol. 18 Issue 52 Pg. 7477-94 (Dec 09 1999) ISSN: 0950-9232 [Print] England
PMID10602507 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)
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
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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