Regulated expression of Wnt family members during proliferation of C57mg mammary cells.

At least six members of the Wnt gene family are expressed in the murine mammary gland during growth and differentiation, whereas several other Wnt family members participate in malignant transformation of this tissue. We have used the C57mg mammary cell line, which naturally expresses the Wnt-4 and Wnt-5a genes, to examine Wnt gene expression during proliferation. The data show that the growth factors basic fibroblast growth factor, transforming growth factor beta 1, and epidermal growth factor are mitogenic for C57mg cells, and partial transformation by Wnt-1 can substitute for the proliferative signal provided by these factors. Several different mitogenic stimuli selectively down-modulate the levels of endogenous Wnt-4 and Wnt-5a RNA in C57mg cells. Partial transformation by either Wnt-1 or Wnt-2 is accompanied by a dramatic decrease in Wnt-4 RNA and a small decrease in Wnt-5a RNA. Mitogenic stimulation by basic fibroblast growth factor or partial transformation by Int-2, a fibroblast growth factor family member, also leads to a selective decrease in the levels of endogenous Wnt RNA. No expression of the Wnt-4 and Wnt-5a genes is detectable in C57mg cells that are fully transformed by the activated tyrosine kinase oncogene Neu. In contrast, overexpression of Wnt-5a in C57mg cells does not lead to a transformed phenotype and is not accompanied by a decrease in endogenous Wnt-4 RNA levels. Overexpression of Wnt-5a does lead to a small decrease in endogenous Wnt-5a levels, perhaps through autoregulation. These data indicate that Wnt-4 and Wnt-5a expression in mammary cells is responsive to growth regulatory signals, and the down-modulation of expression of either or both genes correlates with cell proliferation. The inverse correlation between expression of the endogenous Wnt genes and cell proliferation suggests that Wnt-4 and Wnt-5a may participate in restricting the proliferation of C57mg cells.