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We show that expression of MTA3 inhibits ductal branching in virgin and pregnant murine transgenic mammary glands.MTA3 also suppresses the Wnt4 pathway and, thus, these findings parallel phenotypic changes in Wnt4-null mice.MTA3 represses Wnt4 transcription and Wnt4 secretion, inhibiting Wn -target genes in mammary epithelial cells.Accordingly, knockdown of endogenous MTA3 stimulates Wnt4 expression and Wnt cellular targets.The MTA3-NuRD (nucleosome remodeling and deacetylase) complex physically interacts with the Wnt4 chromatin in an HDAC-dependent manner, leading to suppression of the Wnnt4 gene and Wnt4-dependent morphogenesis.These findings identify MTA3 as an upstream physiologic repressor of Wnt4 in mammary epithelial cells.