WNT-B-10 DIRECTS HYPERMORPHIC DEVELOPMENT AND TRANSFORMATION IN MAMMARY-GLANDS OF MALE AND FEMALE MICE

Wnt-10b is expressed during the formation of the mammary rudiment in m ouse embryos and its expression continues through puberty when the mam mary ductal pattern is established under control of ovarian steroids, Recently, viral activation of the Wnt-10b locus has linked its overexp ression to mammary tumor formation, suggesting a role for Wnt-10b in p atterning and growth-regulation of the mammary gland, To test this not ion, we created lines of transgenic mice that express elevated levels of Wnt-10b under the control of the MMTV promoter/enhancer. Overexpres sion of this gene resulted in profound developmental alterations in th e mammary gland, including expanded glandular development and the prec ocious appearance of alveoli in virgin females, Moreover, transgenic m ale mice also exhibited dramatic mammary development involving highly branched mammary ducts and gynecomastia. Aberrant expression of Wnt-10 b in the mammary rudiments of males evidently bypasses the normal requ irement for ovarian hormonal control in stimulating mammary ductal gro wth and the repressive effects of androgens, In addition to these deve lopmental effects, transgenic mice of both sexes were highly susceptib le to the development of mammary adenocarcinomas, Such tumors arose in a solitary manner indicating that Wnt-10b is a proto-oncogene which p rovides a necessary, but insufficient signal for oncogenesis, Relevant to this, there was no evidence of amplified expression of FGF mRNAs i n these tumors though the Fgf's are a class of genes often implicated as collaborators in Wilt-mediated tumor formation, Indeed, co-expressi on of MMTV-Wnt-10b and MMTV-FGF-3/int-2 resulted in sterile offspring with highly disorganized mammary epithelium, demonstrating a potent in teraction between their respective developmental pathways, These resul ts suggest that Wnt-10b, or other Wilt genes expressed early in mammar y development, play a role in regulating sexual dimorphism and show po tent transforming activity when overexpressed.