KERATINOCYTE GROWTH-FACTOR INDUCES MAMMARY AND PROSTATIC HYPERPLASIA AND MAMMARY ADENOCARCINOMA IN TRANSGENIC MICE

The kinetics of solitary mammary tumor formation in transgenic mice be aring the MMTV-int-2 (fgf3) fusion gene suggest that several genetic e vents are required for tumorigenesis, In an effort to identify element s that could contribute to this oncogenic process, we used differentia l display PCR to identify gene products that are strongly and specific ally induced in int-2 mammary tumors, Using this approach we identifie d a member of the FGF family, kgf (fgf7), as a gene that is strongly u pregulated in an int-2-containing mammary tumor, Since int-2 and kgf s trongly bind the same receptor, the IIIb isoform of FGFR2, it is possi ble that their joint expression, one as a transgene, the other as an a ctivated gene, might reinforce the same mitogenic pathway, To test thi s possibility, we created transgenic mice that carry kgf as a transgen e gene under the control of the MMTV promoter/enhancer, Female mice ca rrying this transgene develop a very dramatic mammary epithelial hyper plasia and go on to develop solitary, metastatic adenocarcinomas of th e mammary gland, Consistent with a common signalling pathway, the MMTV -kgf-induced hyperplasia has the morphologic characteristics of that s een in the MMTV-int-2 mice, Male mice also develop hyperplasia of the male genital tract, including the seminal vesicle, the vas deferens an d the prostate, Thus KGF can act as a potent proliferative inducer in mammary and specific urogenital tissue and can contribute to the devel opment of adenocarcinoma of the mammary gland in a manner strongly rem iniscent of receptor-related ligand, int-2.