Normal mammary gland development requires systemic hormones in conjunction with the correct temporal and spatial expression of local growth factors. Disruption of these expression patterns can result in abnormal growth and tumorigenesis. Fibroblast growth factors (FGFs) are candidates for factors which locally regulate mammary gland growth and may potentially mediate the effects of mammogenic steroids. FGFs have traditionally been associated with angiogenesis, a critical process for tumor growth, and FGF-3 (int-2) is a mammary oncogene. Recently, the investigator has demonstrated the differential gene expression of FGF family members in mammary development suggesting FGFs have multiple regulatory roles in mammary development. Several studies have also reported evidence that FGF-I mediates the effects of estrogen or progesterone in tissue culture cells. The goal of this proposal is to investigate the putative role for FGFs as partial mediators of steroid action in the mouse mammary gland, to determine the roles of the FGFs in controlling growth, differentiation and tumorigenesis. and to design effective methodologies for specifically blocking FGF pathways, thereby inhibiting the initiation, and progression of breast cancer. Experiments will focus on the effects of disrupting normal FGF levels and FGF receptor interactions in mammary gland development. Endocrine ablation and replacement studies will be performed to determine the effect of estrogen (E) and progesterone (P) on FGF levels. The ability for FGFs to replace E and P will be analyzed in mammary glands from estrogen-ablated animals. The effects of overexpression of FGF-I, F(3F-2, and FGF-4 will be determined, and FGF action in the gland will be prevented by blocking specific FGF effects using dominant-negative receptor mutants, antisense DNA, and blocking peptides. A combination of transgenic, gene therapy, and implant technology will be used. The specific growth and morphogenic effects of the FGFs on mammary development will be distinguished from the stimulation of angiogenesis by using general inhibitors of angiogenesis that do not effect FGF action in the gland. The successful methodologies for specifically targeting FGF pathways with inhibitors, possibly in combination with anti-angiogenic factors, will then be applied to the prevention of breast cancer and the inhibition of tumor growth and progression.
