Aberrant low expression of p85α in stromal fibroblasts promotes breast cancer cell metastasis through exosome-mediated paracrine Wnt10b

P85 alpha, which acts as a tumour suppressor, is frequently found to be downregulated in various human cancers. However, the role of p85 alpha in the tumour microenvironment is unknown. Here, we report that aberrantly low expression of p85 alpha in breast cancer stroma is clinically relevant to breast cancer disease progression. Stromal fibroblasts can acquire the hallmarks of cancer-associated fibroblasts (CAFs) as a result of the loss of p85 alpha expression. Paracrine Wnt10b from p85 alpha-deficient fibroblasts can promote cancer progression via epithelial-to-mesenchymal transition (EMT) induced by the canonical Wnt pathway. Moreover, exosomes have a key role in paracrine Wnt10b transport from fibroblasts to breast cancer epithelial cells. Our results reveal that p85 alpha expression in stromal fibroblasts haves a crucial role in regulating breast cancer tumourigenesis and progression by modifying stromal-epithelial crosstalk and remodelling the tumour microenvironment. Therefore, p85 alpha can function as a tumour suppressor and represent a new candidate for diagnosis, prognosis and targeted therapy.