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Overexpression of Cyclin D1 Contributes to Malignancy by Up-Regulation of Fibroblast Growth Factor Receptor 1 via the pRB/E2F Pathway¹

Department of Biosciences and Informatics, Faculty of Science and Technology, Keio University, Yokohama 223-8522, Japan [E. T., H. M., Y. M., M. I.]; Department of Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka 537-8511, Japan [Y. D.]; and Herbert Irving Comprehensive Cancer Center and Department of Medicine, Columbia University, College of Physicians and Surgeons, New York, New York 10032 [I. B. W.]

Overexpression of cyclin D1 due to gene rearrangement, gene amplification, or simply increased transcription occurs frequently in several types of human cancers. However, overexpression of cyclin D1 in cell culture system is insufficient, by itself, to cause malignant transformation. In the present study, we found that when rodent fibroblasts that overexpress cyclin D1, but not normal fibroblasts, were treated with basic fibroblast growth factor (bFGF), there was enhanced cell cycle progression, extracellular signal-regulated kinase 2 activation, induction of anchorage-independent growth, and enhanced invasion of a Matrigel barrier. These enhanced responses to bFGF appear to be due to increased expression of fibroblast growth factor receptor 1, at both the mRNA and protein levels, in the cyclin D1-overexpressing cells. We obtained evidence that this increase in fibroblast growth factor receptor 1 expression is mediated through cyclin D1 activation of the pRB/E2F pathway. Taken together, these results suggest that in vivo cyclin D1 overexpression can enhance tumor progression, at least in part, by potentiating the stimulatory efforts of bFGF, which is often produced by stromal cells, and the growth of adjacent tumor cells.

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