P38 MAPK inhibits breast cancer metastasis through regulation of stromal expansion

p38 MAPK signaling controls cell growth, proliferation and the cell cycle under stress conditions. However, the function of p38 activation in tumor metastasis is still not well understood. We report that p38 activation in breast cancer cells inhibits tumor metastasis but does not substantially modulate primary tumor growth. Stable p38 knockdown in breast cancer cells suppressed NF-κB p65 activation, inhibiting miR-365 expression and resulting in increased IL-6 secretion. The inhibitory effect of p38 signaling on metastasis was mediated by suppression of mesenchymal stem cell (MSC) migration to the primary tumor and sites of metastasis, where MSCs can differentiate into cancer-associated fibroblasts to promote tumor metastasis. The migration of MSCs to these sites relies on CXCR4-SDF1 signaling in the tumor microenvironment. Analysis of human primary and metastatic breast cancer tumors showed that p38 activation was inversely associated with IL-6 and vimentin expression. This study suggests that combination analysis of p38 MAPK and IL-6 signaling in patients with breast cancer may improve prognosis and treatment of metastatic breast cancer. What's new? While p38 MAPK signaling plays an important role in controlling cell growth, proliferation, and the cell cycle under stress conditions, the function of p38 activation in tumor metastasis is still not well understood. This study showed that abolishing p38 signaling in murine breast cancer cells promoted tumor metastasis through stromal expansion controlled by miRNA-365 mediated IL-6 signaling. In human primary and metastatic breast cancer tumors, p38 activation was inversely correlated with IL-6 and vimentin expression. This study suggests that p38 MAPK and IL-6 could be prognostic indicators as well as potential therapeutic targets in metastatic breast cancer.