Enhanced invasion and tumor growth of fibroblast growth factor 8b-overexpressing MCF-7 human breast cancer cells

• Published in: Cancer research (Chicago, Ill.) Vol. 61; no. 10; pp. 4229 - 4237
• Main Authors: RUOHOLA, Johanna K, VIITANEN, Tiina P, VALVE, Eeva M, SEPPÄNEN, Jani A, LOPONEN, Niina T, KESKITALO, Jaakko J, LAKKAKORPI, Päivi T, HÄRKÖNEN, Pirkko L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15-05-2001
• Subjects: Animals; Biological and medical sciences; Breast Neoplasms - blood supply; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Adhesion - physiology; Cell Division - drug effects; Cell Division - physiology; Dissemination; Female; Fibroblast Growth Factor 8; fibroblast growth factor 8^b; Fibroblast Growth Factors - biosynthesis; Fibroblast Growth Factors - genetics; Fibroblast Growth Factors - metabolism; Humans; Medical sciences; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasm Invasiveness; Neoplasms, Hormone-Dependent - genetics; Neoplasms, Hormone-Dependent - metabolism; Neoplasms, Hormone-Dependent - pathology; Neovascularization, Pathologic - metabolism; Protein Isoforms - biosynthesis; Protein Isoforms - genetics; Protein Isoforms - pharmacology; Receptors, Fibroblast Growth Factor - biosynthesis; Receptors, Fibroblast Growth Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Transfection; Transplantation, Heterologous; Tumor cell; Tumors; Cell proliferation; Fibroblast growth factor; Molecular form; Gene product; Gene overexpression; Carcinogenesis; Transfection; Established cell line; Tumor progression; Mammary gland; Neovascularization; Mechanism of action; Tumor cell; Human; Rodentia; Malignant tumor; Gene expression; In vitro; Invasion; Mammary gland diseases; In vivo; Vertebrata; Growth factor receptor; Mammalia; Mouse; Animal
• ISSN: 0008-5472; 1538-7445

Fibroblast growth factor 8 (FGF-8) is a secreted heparin-binding protein, which has mitogenic and transforming activity. Increased expression of FGF-8 has been found in human breast cancer, and it has a potential autocrine role in its progression. Human FGF-8 is alternatively spliced to generate four protein isoforms (a, b, e, and f). Isoform b has been shown to be the most transforming. In this work, we studied the role of FGF-8b in the growth (in vitro and in vivo) of MCF-7 human breast cancer cells, which proliferate in an estrogen-dependent manner. Constitutive overexpression of FGF-8b in MCF-7 cells down-regulated FGF-8b-binding receptors FGF receptor (FGFR) 1IIIc, FGFR2IIIc, and FGFR4 found to be expressed in these cells. FGF-8b overexpression led to an increase in the anchorage-independent proliferation rate in suspension culture and colony formation in soft agar, when MCF-7 cells were cultured with or without estradiol. FGF-8b also provided an additional growth advantage for cells stimulated with estradiol. In addition, FGF-8b-transfected cells invaded more actively through Matrigel than did control cells. This was possibly due to the increased secretion of matrix metalloproteinase 9. In vivo, FGF-8b-transfected MCF-7 cells formed faster growing tumors than vector-only-transfected cells when xenografted into nude mice. The tumors formed by FGF-8b-transfected cells were more vascular than the tumors formed by vector-only-transfected cells. In conclusion, FGF-8b expression confers a growth advantage to MCF-7 breast carcinoma cells, both in vitro and in vivo. In addition to stimulation of proliferation, this growth advantage probably arises from increased invasion and tumor vascularization induced by FGF-8b. The results suggest that FGF-8b signaling may be an important factor in the regulation of tumorigenesis and progression of human breast cancer.