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Bone morphogenetic protein 4 (BMP4) is required for migration and invasion of breast cancer

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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.

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Abbreviations

BMP4:

Bone morphogenetic proteins 4

MMP-1:

Matrix metalloproteinase-1

CXCR4:

C-X-C chemokine receptor type 4

CXCL12:

Chemokine (C-X-C motif) ligand 12, SDF-1

OPG:

Osteoprotegerin

RANKL:

Receptor activator of NF-kB ligand

GFP:

Green fluorescent protein

RFP:

Red fluorescent protein

RT-PCR:

Reverse transcriptase-polymerase chain reaction

qPCR:

Real-time quantitative PCR

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Acknowledgments

The authors thank Dr. T.-C. He of The University of Chicago Medical Center for providing the cell lines, vectors, and technical support. The above study was supported by research grants from Chongqing Public Health Bureau (Grant# 2010-2-157, DG) and Chongqing Natural Science Foundation (Grant# 2010BB5100, JYH),China.

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The authors report no conflicts of interest.

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  1. Department of Surgery, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China

    Dan Guo & Jianping Gong

  2. Department of Molecular Biology and Biochemistry, School of Basic Medical Sciences, Chongqing Medical University, Chongqing, China

    Jiayi Huang

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  1. Dan Guo
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Correspondence to Jianping Gong.

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Guo, D., Huang, J. & Gong, J. Bone morphogenetic protein 4 (BMP4) is required for migration and invasion of breast cancer. Mol Cell Biochem 363, 179–190 (2012). https://doi.org/10.1007/s11010-011-1170-1

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