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 murin e mammary gland during growth and differentiation, whereas several oth er Wnt family members participate in malignant transformation of this tissue. We have used the C57mg mammary cell line, which naturally expr esses the Wnt-4 and Wnt-5a genes, to examine Wnt gene expression durin g proliferation. The data show that the growth factors basic fibroblas t growth factor, transforming growth factor beta1, and epidermal growt h factor are mitogenic for C57mg cells, and partial transformation by Wnt-1 can substitute for the proliferative signal provided by these fa ctors. Several different mitogenic stimuli selectively down-modulate t he levels of endogenous Wnt-4 and Wnt-5a RNA in C57mg cells. Partial t ransformation by either Wnt-1 or Wnt-2 is accompanied by a dramatic de crease in Wnt-4 RNA and a small decrease in Wnt-5a RNA. Mitogenic stim ulation by basic fibroblast growth factor or partial transformation by Int-2, a fibroblast growth factor family member, also leads to a sele ctive decrease in the levels of endogenous Wnt RNA. No expression of t he 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 transform ed 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 i ndicate that Wnt-4 and Wnt-5a expression in mammary cells is responsiv e to growth regulatory signals, and the down-modulation of expression of either or both genes correlates with cell proliferation. The invers e correlation between expression of the endogenous Wnt genes and cell proliferation suggests that Wnt-4 and Wnt-5a may participate in restri cting the proliferation of C57mg cells.