This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wang, H. Articles by Wieder, R. Search for Related Content PubMed PubMed Citation Articles by Wang, H. Articles by Wieder, R.

Basic Fibroblast Growth Factor Causes Growth Arrest in MCF-7 Human Breast Cancer Cells while Inducing both Mitogenic and Inhibitory G₁ Events¹

Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey 07103 [H. W., R. W.], and Departments of Medicine [M. R., A. D., J. M.] and Radiation Oncology [E. F., J. Y.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

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 inhibitor correlated with a bFGF dose- and time-dependent increase in the levels of cdk inhibitor p21^WAF1/CIP1 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.

¹ Supported in part by Career Development Award DAMD17-94-J-4463 from the United States Army Breast Cancer Research Program (to R. W.) and Grant 16–95 from the Foundation of the University of Medicine and Dentistry of New Jersey (to R. W.).

² To whom requests for reprints should be addressed, at University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Division of Medical Oncology, MSB I-689, 185 South Orange Avenue, Newark, NJ 07103. Phone: (201) 982-4871; Fax: (201) 982-2384.

Received 10/17/96. Accepted 3/ 1/97.

This article has been cited by other articles:

				S. Song, B. Yu, Y. Wei, M. G. Wientjes, and J. L.-S. Au Low-Dose Suramin Enhanced Paclitaxel Activity in Chemotherapy-Naive and Paclitaxel-Pretreated Human Breast Xenograft Tumors Clin. Cancer Res., September 15, 2004; 10(18): 6058 - 6065. [Abstract] [Full Text] [PDF]

				R. Korah, M. Boots, and R. Wieder Integrin {alpha}5{beta}1 Promotes Survival of Growth-Arrested Breast Cancer Cells: An in Vitro Paradigm for Breast Cancer Dormancy in Bone Marrow Cancer Res., July 1, 2004; 64(13): 4514 - 4522. [Abstract] [Full Text] [PDF]

				O. Rozenblatt-Rosen, E. Mosonego-Ornan, E. Sadot, L. Madar-Shapiro, Y. Sheinin, D. Ginsberg, and A. Yayon Induction of chondrocyte growth arrest by FGF: transcriptional and cytoskeletal alterations J. Cell Sci., January 2, 2002; 115(3): 553 - 562. [Abstract] [Full Text] [PDF]

				S. M. Duplan, Y. Theoret, and R. Kenigsberg Antitumor Activity of Fibroblast Growth Factors (FGFs) for Medulloblastoma May Correlate with FGF Receptor Expression and Tumor Variant Clin. Cancer Res., January 1, 2002; 8(1): 246 - 257. [Abstract] [Full Text] [PDF]

				J. K. Ruohola, T. P. Viitanen, E. M. Valve, J. A. Seppänen, N. T. Loponen, J. J. Keskitalo, P. T. Lakkakorpi, and P. L. Härkönen Enhanced Invasion and Tumor Growth of Fibroblast Growth Factor 8b-overexpressing MCF-7 Human Breast Cancer Cells Cancer Res., May 1, 2001; 61(10): 4229 - 4237. [Abstract] [Full Text]

				R. Clarke, F. Leonessa, J. N. Welch, and T. C. Skaar Cellular and Molecular Pharmacology of Antiestrogen Action and Resistance Pharmacol. Rev., March 1, 2001; 53(1): 25 - 72. [Abstract] [Full Text] [PDF]

				L.-M. Sturla, G. Westwood, P. J. Selby, I. J. Lewis, and S. A. Burchill Induction of Cell Death by Basic Fibroblast Growth Factor in Ewing's Sarcoma Cancer Res., November 1, 2000; 60(21): 6160 - 6170. [Abstract] [Full Text]

				T. Iwata, L. Chen, C.-l. Li, D. A. Ovchinnikov, R. R. Behringer, C. A. Francomano, and C.-X. Deng A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos Hum. Mol. Genet., July 1, 2000; 9(11): 1603 - 1613. [Abstract] [Full Text] [PDF]

				R. M. Korah, V. Sysounthone, Y. Golowa, and R. Wieder Basic Fibroblast Growth Factor Confers a Less Malignant Phenotype in MDA-MB-231 Human Breast Cancer Cells Cancer Res., February 1, 2000; 60(3): 733 - 740. [Abstract] [Full Text]

				R. G. Pestell, C. Albanese, A. T. Reutens, J. E. Segall, R. J. Lee, and A. Arnold The Cyclins and Cyclin-Dependent Kinase Inhibitors in Hormonal Regulation of Proliferation and Differentiation Endocr. Rev., August 1, 1999; 20(4): 501 - 534. [Abstract] [Full Text] [PDF]

				T. Aikawa, G. V. Segre, and K. Lee Fibroblast Growth Factor Inhibits Chondrocytic Growth through Induction of p21 and Subsequent Inactivation of Cyclin E-Cdk2 J. Biol. Chem., July 27, 2001; 276(31): 29347 - 29352. [Abstract] [Full Text] [PDF]