Fibroblast growth factor 3 is tumorigenic for mouse mammary cells orthotopically implanted in nude mice

Fibroblast growth factor-3 (Fgf-3) is involved in mouse mammary tumorigenesis since the Fgf-3 gene is a main target for mouse mammary tumor virus (MMTV) insertional activation. Its action has been correlated with the appearance of pregnancy-dependent tumors. We describe here the effects on normal mouse mammary EF43 cells of the short Fgf-3 protein form which enters the secretory pathway. The genes, Fgf-3 AUG or Fgf-4 for comparison, were introduced in the mammary cells by means of retroviral vectors. Fgf-3 expression did not modify EF43 cell morphology, had no effect on growth in soft agar nor on the inhibitory action exerted on cell growth by TGF-beta 1; however, it allowed the cells to grow under low serum conditions in the absence of insulin and EGF. The Fgf-3-expressing cells were not tumorigenic in nude mice when injected s.c., but tumors developed when the cells were implanted in the mammary gland. The tumors appeared after some latency; they had a slow growth phase followed by a phase of increased growth rate. An identical tumoral growth pattern was observed in ovariectomized nude mice. These results show that the secreted Fgf-3 form can initiate tumorigenesis and that the induced tumors are hormone-independent. The mammary-gland environment, however, is required for the EF43 cells to grow and differentiate. During that process, which resembles natural cell growth during mammary-gland development at pregnancy, the cells could pass through a stage which is specifically sensitive to Fgf-3.