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

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Abstract
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‐β; 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. © 1995 Wiley‐Liss, Inc.