ACTIVATION OF FGF8 IN S115 MOUSE MAMMARY-TUMOR CELLS IS ASSOCIATED WITH GENOMIC INTEGRATION OF MOUSE MAMMARY-TUMOR VIRUS

Fgf8 is an embryonally expressed mitogenic fibroblast growth factor wh ich has transforming capacity. It is expressed in S115 mouse mammary t umor cells (S115 cells) and in parental tumors of DD/Sio mice as well as in some human breast and prostate cancer cell lines. In S115 cells androgens induce the expression of Fgf8 which seems to be associated w ith the androgen-maintained malignant phenotype of the cells. S115 cel ls also contain and express Mtv proviruses known to insertionally acti vate oncogenes in other tumor cells. Here we studied the possibility o f insertional activation of Fgf8 in S115 cells by MMTV proviral integr ation. We demonstrate by Southern blotting that the genomic DNA from D D/Sio tumors and S115 cells contains Mtv-sequences (Mtv-6 and Mtv-17) which are not found in the DNA from spleen or liver of the DD/Sio mice . In addition, the newly integrated Mtv-g was localized to the DNA fra gment containing the Fgf8 gene. Furthermore, the expression of Fgf8 mR NA in DD/Sio tumors and S115 cells was not found in mammary gland or s pleen and liver of DD/Sio mice. In S115 cells, Fgf8 mRNA expression wa s induced in parallel to MMTV mRNA by androgen and glucocorticoids whi ch supports the possibility that Fgf8 is controlled by the steroid-reg ulated MMTV-LTR. In conclusion, our data provide evidence that the ins ertion of MMTV into the DD/Sio tumor DNA is associated with the transc riptional activation of Fgf8 in DD/Sio tumor and consequently in S115 mouse mammary tumor cells. (C) 1998 Academic Press.