Analysis of Multistep Mammary Tumorigenesis in Wnt-1 Transgenic Mice
Final rept. 1 Sep 1994-31 Aug 1998
CHILDREN'S HOSPITAL LOS ANGELES CA
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Breast cancer like all cancers, is a multi step process involving the sequential acquisition of genetic alterations over a period of time. Studying this process in humans is a prolonged and arduous task therefore, animal models are a desirable alternative. We have used a Wntl transgenic mouse model to study the multiple genetic events in mammary cancer development. We infected these transgenic mice with the mouse mammary tumor virus MMTV to accelerate tumorigenesis and to molecularly tag proto-oncogenes that are activated in the resulting tumors and that cooperate with Wnt- 1 in mammary tumorigenesis. By examination of the tumors that lack activation of genes that are usual targets of MMTV insertions, we identified a common insertion locus for MMTV and determined the activated gene in this locus to be another member of the FGF family, Fgf88. Fgf8 is transcriptionaly activated in 50 of the tumors from infected Wntl transgenic mice in comparison to the lack of Fgf8 RNA in other tumors and mammary tissues, suggesting a strong oncogenic cooperation between Fgf8 and Wntl in mammary tumorigenesis. Fgf8 induced apoptosis of mammary epithelial cells as evidenced by nuclear condensation and fragmentation and oligonucleosomal laddering. Overexpression of the anti-apoptotic gene bcl2 in these cells transiently rescued or delayed the apoptosis induced by FGFs. These results describe a new property for FGFs and suggest that these growth factors play very important roles in regulating cell growth and death both in normal development as well as in pathological conditions like cancer.
- Anatomy and Physiology
- Medicine and Medical Research