Basic fibroblast growth factor causes growth arrest in MCF-7 human breast cancer cells while inducing both mitogenic and inhibitory G(1) events Journal Article

Authors: Wang, H.; Rubin, M.; Fenig, E.; DeBlasio, A.; Mendelsohn, J.; Yahalom, J.; Wieder, R.
Article Title: Basic fibroblast growth factor causes growth arrest in MCF-7 human breast cancer cells while inducing both mitogenic and inhibitory G(1) events
Abstract: Basic fibroblast growth factor (bFGF), a classical mitogen in fibroblasts and endothelial cells, inhibits the proliferation of MCF-7 and other human breast cancer cell lines. To explain this paradoxic effect, we investigated the effects of bFGF on cyclins and protein members of cyclin complexes that exert positive and negative control on the progression of cells through the G1 phase of the cell cycle. bFGF induced an increase in cyclin D1, cyclin E, and cyclin-dependent kinase 4 (cdk4) protein levels in a bFGF dose-dependent manner. However, bFGF also induced a heat-stable, transferable cytoplasmic factor in MCF-7 cells that inhibited the histone H1 kinase activity of reconstituted cyclin E-cdk2 and cyclin A-cdk2 complexes from Mv1Lu mink lung epithelial cells. The appearance of this inhibit or correlated with a bFGF dose- and time-dependent increase in the levels of cdk inhibitor p21(WAF1/CIP1) of mRNA and protein. The increase in the level of p21(WAF1/CIP1) was associated with the disappearance of the rapidly migrating, activated form of cdk2 from cell lysates, dephosphorylation of the retinoblastoma protein (Rb), and a decrease in cyclin A levels. These changes were represented in the cyclin D1 and E complexes by an increased association with p21(WAF1/CIP1), proliferating cell nuclear antigen (PCNA), and the inactive form of cdk2, without an absolute change in cellular PCNA levels and by a switch in the association of cyclin D1 complexes with the hyperphosphorylated form to the dephosphorylated form of Rb. These experiments demonstrate that stimulation of MCF-7 cells with bFGF, although resulting in up-regulation of G1 proteins responsible for mitogenic events, also induces a concomitant decrease in cyclin A levels and an increase in p21(WAF1/CIP1) mRNA and protein and results in inactivation of cdk2, dephosphorylation of Rb, and a segregation of PCNA to the G1 cyclin complexes. The dual, conflicting signaling by bFGF results in a net inhibitory phenotype in these cells. These experiments suggest a pleiotropic role for bFGF in breast cancer.
Keywords: controlled study; protein phosphorylation; human cell; proto-oncogene proteins; flow cytometry; mitosis; cell cycle; breast cancer; protein kinases; cancer cell culture; tumor cells, cultured; time factors; fibroblast growth factor 2; blotting, western; messenger rna; oncogene proteins; dna, neoplasm; epithelium cell; cyclin-dependent kinase inhibitor p21; cycline; cyclin d1; cyclin-dependent kinases; cyclins; cyclin a; cyclin dependent kinase; cyclin dependent kinase inhibitor; retinoblastoma protein; protein p21; cell cycle g1 phase; cyclin e; cyclin-dependent kinase 4; growth inhibition; growth inhibitors; basic fibroblast growth factor; lung alveolus epithelium; mitogenicity; humans; human; female; priority journal; article; aphidicolin; protamine kinase
Journal Title: Cancer Research
Volume: 57
Issue: 9
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 1997-05-01
Start Page: 1750
End Page: 1757
Language: English
PUBMED: 9135019
PROVIDER: scopus
Notes: Article -- Export Date: 17 March 2017 -- Source: Scopus
Citation Impact
MSK Authors
  1. Joachim Yahalom
    461 Yahalom