Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines

Interactions between neoplastic and stromal cells contribute to tumor progression. Wnt genes, involved in cell migration and often deregulated in cancers, are attractive candidates to regulate these effects. We have recently shown that coculture of breast cancer cells with macrophages enhances invasiveness via matrix metal loproteases and TNF-alpha. Here we demonstrate that coculture of MCF-7 cells and macrophages leads to up-regulation of Writ 5a in the latter. This was accompanied by activation of AP-1/c-Jun in MCF-7. Recombinant Writ 5a mimicked the coculture effect. Writ 5a was also detectable in tumor-associated macrophages in primary breast cancers. Experiments with agonists and antagonists of Writ signaling revealed that a functional canonical pathway in the tumor cells was a necessary prerequisite; however, noncanonical signaling via Writ 5a and the Jun-N-terminal kinase pathway was critical for invasiveness. It was also responsible for induction of matrix metalloprotease-7, known to release TNF-alpha. All these effects could be antagonized by dickkopf-1. Our results indicate that Wnt 5a is essential for macrophage-induced invasiveness, because it regulates tumor cell migration as well as proteolytic activity of the macrophages. The function of Writ 5a as either a suppressor or promoter of malignant progression seems to be modulated by intercellular interactions. Writ 5a detection in tumor-associated macrophages in breast cancer biopsies supports the assumption that similar events play a role in vivo.