title: p38 MAPK inhibits breast cancer metastasis through regulation of stromal expansion.
abstract: 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.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Bangxing
authors.initials: B
authors.lastname: Hong
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.forename: Mingjun
authors.initials: M
authors.lastname: Zhang
authors.forename: Jingda
authors.initials: J
authors.lastname: Xu
authors.forename: Yong
authors.initials: Y
authors.lastname: Lu
authors.forename: Yuhuan
authors.initials: Y
authors.lastname: Zheng
authors.forename: Jianfei
authors.initials: J
authors.lastname: Qian
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Chang
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
mesh_terms: D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary; D020935:MAP Kinase Signaling System; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000378:metabolism; D009368:Neoplasm Transplantation; D019718:Receptors, CXCR4 / Q000378:metabolism; D059016:Tumor Microenvironment; D014746:Vimentin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology*
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D015850:Interleukin-6; C000589043:MIRN365 microRNA, mouse; D035683:MicroRNAs; D019718:Receptors, CXCR4; D014746:Vimentin; D048051:p38 Mitogen-Activated Protein Kinases
keywords: IL-6; breast cancer; metastasis; microRNA; p38 MAPK