MAPK11 in breast cancer cells enhances osteoclastogenesis and bone resorption

• Published in: Biochimie Vol. 106; pp. 24 - 32
• Main Authors: He, Zhimin, He, Jin, Liu, Zhiqiang, Xu, Jingda, Yi, Sofia F., Liu, Huan, Yang, Jing
• Format: Journal Article
• Language: English
• Published: France Elsevier B.V 01.11.2014
• Subjects: Animals; Blotting, Western; Bone and Bones - metabolism; Bone and Bones - pathology; Bone resorption; Bone Resorption - genetics; Bone Resorption - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line, Tumor; Chemokine CCL2 - genetics; Chemokine CCL2 - metabolism; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; MAPK11; MCF-7 Cells; MCP-1; Mice, SCID; Mitogen-Activated Protein Kinase 11 - genetics; Mitogen-Activated Protein Kinase 11 - metabolism; Osteoclasts; Osteoclasts - metabolism; Osteogenesis - genetics; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Tissue Array Analysis; Transplantation, Heterologous; MCP-1; RANKL; IL; M-CSF; OPG; preOC; Breast cancer; TRAP; MAPK; p38δ; p38γ; p38β; p38α; Bone resorption; MAPK11; pp38; OC; shRNA; Osteoclasts; HLA
• ISSN: 0300-9084; 1638-6183
• DOI: 10.1016/j.biochi.2014.07.017

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 p38 MAPK (p38) isoform MAPK11 (p38β) is expressed in breast cancer cells. By using specific small hairpin RNAs for MAPK11, we demonstrated that p38β-mediated p38 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 p38β, induced osteoclast differentiation and bone resorption. In contrast, knockdown of p38β in breast cancer cells reduced osteoclast differentiation in vitro and reduced bone destruction in severe combined immunodeficiency (SCID) mouse models. The knockdown of p38β did not affect tumor growth or survival or the ability of cancer cells to home to bone. Furthermore, our results showed that p38β 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 p38β and its product MCP-1 may be a viable approach to treat or prevent bone destruction in patients with bone-metastatic breast cancer. •MAPK11 is highly expressed in the metastatic breast cancer patients and in the breast cancer cell lines.•MAPK11 is responsible to breast cancer-induced osteolytic bone destruction.•Upregulated MCP-1 activates osteoclast differentiation and activity.•Novel molecular mechanism of breast cancer cell-induced osteolytic bone destruction.