MAPK11 in breast cancer cells enhances osteoclastogenesis and bone resorption.

[severe combined immunodeficiency]

Breast cancer cells frequently metastasize to bone and induce osteolytic bone destruction in patients . These metastases cause severe bone pain , high risk of fractures and hypercalcemia , and are essentially incurable and fatal . Recent studies show that breast cancer cells in bone activate osteoclastogenesis and bone resorption . However the underlying mechanism is poorly understood . This study shows that the p 38 MAPK (p 38 ) isoform MAPK 11 (p 38 Î² ) is expressed in breast cancer cells . By using specific small hairpin RNAs for MAPK 11 , we demonstrated that p 38 Î²-mediated p 38 activity in breast cancer cells is responsible for breast cancer -induced osteolytic bone destruction . The addition of conditioned media from breast cancer cell lines MDA-MB -231 and MDA-MB -468 , which have high expression of p 38 Î² , induced osteoclast differentiation and bone resorption . In contrast , knockdown of p 38 Î² in breast cancer cells reduced osteoclast differentiation in Â vitro and reduced bone destruction in severe combined immunodeficiency (SCID ) mouse models . The knockdown of p 38 Î² did not affect tumor growth or survival or the ability of cancer cells to home to bone . Furthermore , our results showed that p 38 Î² upregulated the expression and secretion of monocyte chemotactic protein-1 (MCP-1 ) in breast cancer cells , and upregulated MCP-1 activates osteoclast differentiation and activity . This study elucidates a novel molecular mechanism of breast cancer cell-induced osteolytic bone destruction . This study also indicates that targeting breast cancer cell p 38 Î² and its product MCP-1 may be a viable approach to treat or prevent bone destruction in patients with bone -metastatic breast cancer .