Wnt5a is required for proper mammary gland development and TGF-beta-mediated inhibition of ductal growth.

Transforming growth factor-beta (TGF-beta) plays an essential role in growth and patterning of the mammary gland, and alterations in its signaling have been shown to illicit biphasic effects on tumor progression and metastasis. We demonstrate in mice that TGF-beta (Tgfbeta) regulates the expression of a non-canonical signaling member of the wingless-related protein family, Wnt5a. Loss of Wnt5a expression has been associated with poor prognosis in breast cancer patients; however, data are lacking with regard to a functional role for Wnt5a in mammary gland development. We show that Wnt5a is capable of inhibiting ductal extension and lateral branching in the mammary gland. Furthermore, Wnt5a(-/-) mammary tissue exhibits an accelerated developmental capacity compared with wild-type tissue, marked by larger terminal end buds, rapid ductal elongation, increased lateral branching and increased proliferation. Additionally, dominant-negative interference of TGF-beta signaling impacts not only the expression of Wnt5a, but also the phosphorylation of discoidin domain receptor 1 (Ddr1), a receptor for collagen and downstream target of Wnt5a implicated in cell adhesion/migration. Lastly, we show that Wnt5a is required for TGF-beta-mediated inhibition of ductal extension in vivo and branching in culture. This study is the first to show a requirement for Wnt5a in normal mammary development and its functional connection to TGF-beta.