Wnt5a as an effector of TGFβ in mammary development and cancer.

Wnt5a is a member of the Wingless-related/MMTV-integration family of secreted growth factors, which are involved in a wide range of cellular processes. Wnt signaling can be broadly divided into two categories the canonical, ß-catenin-dependent pathway and the non-canonical ß-catenin-independent pathway. Wnt5a is a non-canonical signaling member of the Wnt family. Loss of Wnt5a is associated with early relapse of invasive breast cancer, increased metastasis, and poor survival in humans. It has been shown that TGF-ß directly regulates expression of Wnt5a in mammary gland and that Wnt5a mediates the effects of TGF-ß on branching during mammary gland development. Here we review the evidence suggesting Wnt5a acts as an effector of TGF-ß actions in breast cancer. It is suggested that the tumor suppressive functions of TGF-ß involve Wnt5a-mediated antagonism of Wnt/ß-catenin signaling and limiting the stem cell population. Interactions between TGF-ß and Wnt5a in metastasis appear to be more complex, and may depend on specific cues from the microenvironment as well as activation of specific intracellular signaling pathways.