HYPERPLASIA OF MOUSE MAMMARY EPITHELIUM INDUCED BY EXPRESSION OF THE WNT-1 (INT-1) ONCOGENE IN RECONSTITUTED MAMMARY-GLAND

We have expressed the Wnt-1 (formerly int-1) oncogene in Balb/c mouse mammary epithelium in vivo, using a tissue reconstitution method in which primary cultures of mammary epithelial cells are infected with a retrovirus vector and then transplanted into mouse mammary fat pads from which the natural epithelium has been removed. Transplants carrying the Wnt-1 gene grew in a hyperplastic pattern, the duct epithelium showing abundant fine side-branches, but without development of clusters of alveoli. The hyperplasias were similar, but not identical, to transplants of normal epithelium in a mid-pregnant host. Transplants of epithelium that expressed Wnt-1 into mammary fat pads of male or ovari-ectomized females grew to form a similar three-dimensional pattern, but the extent of growth, and so presumably the rate of growth, was slower than in intact females, and there were no terminal end buds at the edges of the outgrowths. Thus, although Wnt-1 may enhance growth of epithelium in the male or ovari-ectomized-female environment, it does not restore the major mode of growth in the intact female, the extension of major ducts from terminal end buds. Normal epithelium showed no change in morphology when in close proximity to hyperplasia induced by Wnt-1, confirming the limited range of diffusion of Wnt-1 protein in vivo. Our results are consistent with the hypothesis that Wnt-1 acts principally by mimicking the signal that causes ducts to develop side-branches in pregnancy.