title: Bone morphogenetic protein 4 (BMP4) is required for migration and invasion of breast cancer.
abstract: Bone-morphogenetic proteins (BMPs) play an important role in development and many cellular processes. However, their functional role in the development and progression of breast cancer is not clearly understood. In the present study, we performed a systematic expression analysis of the 14 types of BMPs in 10 human breast cancer cell lines. We found that bone morphogenetic protein 4 (BMP4) was one of the most frequently expressed BMPs. Furthermore, the expression level of BMP4 was maybe correlated with the metastatic potential of the cancer lines. Accordingly, overexpression of BMP4 in the breast cancer cell lines MCF-7 and MBA-MD-231 promoted the migration and invasion phenotypes of the cancer cells, whereas RNAi-mediated knockdown of BMP4 expression inhibited the migration and invasion activities of the cancer cells. To identify the important factors that may mediate the BMP4 functions in breast cancer cells, we analyzed a panel of cancer-related genes, and found that the expression of matrix metalloproteinase-1 (MMP-1) and C-X-C chemokine receptor type 4 (CXCR4) sharply increased at both the mRNA and protein levels in the breast cancer cells overexpressing BMP4. Interestingly, when breast cancer cells MDA-MB-231 or MCF-7 were co-cultured with the osteoblast-like cells MG63 to mimic a bone metastasis microenvironment, BMP4 did not exhibit any significant effect on the expression of OPG or RANKL, two important factors in bone remodeling. BMPs antagonists, Noggin, parallel inhibited breast cancer cell migration and invasion and induced bone remodeling. Taken together, our results strongly suggest that BMP4 may promote the migration and invasion of breast cancer cells, at least in part by up-regulating the expressions of MMP-1 and CXCR4. It is conceivable that novel therapeutics for breast cancer may be developed by targeting BMP4 signaling pathway and/or its important downstream mediators in breast cancer cells.
authors.affiliation: Department of Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Guo
authors.forename: Jiayi
authors.initials: J
authors.lastname: Huang
authors.forename: Jianping
authors.initials: J
authors.lastname: Gong
mesh_terms: D029404:Activin Receptors / Q000235:genetics; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018920:Coculture Techniques; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010006:Osteoblasts / Q000378:metabolism; D053244:Osteoprotegerin / Q000378:metabolism; D010641:Phenotype; D053245:RANK Ligand / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000235:genetics; D013997:Time Factors; D014162:Transfection; D000099176:Noggin Protein
chemical_list: D029404:Activin Receptors; D055415:Bone Morphogenetic Protein 4; D002352:Carrier Proteins; D020781:Matrix Metalloproteinase 1; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; D019718:Receptors, CXCR4; D051785:Smad Proteins; D000099176:Noggin Protein; C525809:BMP4 protein, human; C527276:CXCR4 protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; C522360:MMP1 protein, human