Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis

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Abstract

Breast cancer (BCa) bone metastases cause osteolytic bone lesions, which result from the interactions of metastatic BCa cells with osteoclasts and osteoblasts. Osteoclasts differentiate from myeloid lineage cells. To understand the cell-specific role of transforming growth factor beta (TGF-β) in the myeloid lineage, in BCa bone metastases, MDA-MB-231 BCa cells were intra-tibially or intra-cardially injected into LysMCre/Tgfbr2floxE2/floxE2 knockout (LysMCre/Tgfbr2 KO) or Tgfbr2floxE2/floxE2 mice. Metastatic bone lesion development was compared by analysis of both lesion number and area. We found that LysMCre/Tgfbr2 knockout significantly decreased MDA-MB-231 bone lesion development in both the cardiac and tibial injection models. LysMCre/Tgfbr2 knockout inhibited the tumor cell proliferation, angiogenesis and osteoclastogenesis of the metastatic bones. Cytokine array analysis showed that basic fibroblast growth factor (bFGF) was downregulated in MDA-MB-231-injected tibiae from the LysMCre/Tgfbr2 KO group, and intravenous injection of the recombinant bFGF to LysMCre/Tgfbr2 KO mice rescued the inhibited metastatic bone lesion development. The mechanism by which bFGF rescued the bone lesion development was by promotion of tumor cell proliferation through the downstream mitogen-activated protein kinase (MAPK)-extracellular signal–regulated kinase (ERK)-cFos pathway after binding to the FGF receptor 1 (FGFR1). Consistent with animal studies, we found that in human BCa bone metastatic tissues, TGF-β type II receptor (TβRII) and p-Smad2 were expressed in osteoclasts and tumor cells, and were correlated with the expression of FGFR1. Our studies suggest that myeloid-specific TGF-β signaling-mediated bFGF in the bone promotes BCa bone metastasis.

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Acknowledgements

We thank Dr Julie A Sterling from Vanderbilt University and Dr Yibin Kang from Princeton University for providing cell lines. The Van Andel Research Institute supported this research (VARI start-up to X Li, 53010A). We thank Lisa Turner of the Pathology and Biorepository Core for her pathology expertise, the Vivarium and Transgenics Core for animal technical assistance and Diana Lewis for administrative support. We thank Dr Travis Burgers for the construction of 3D micro-CT pictures. Special thanks to Dr Mary E Winn from the Bioinformatics and Biostatistics Core for her great help in answering statistical questions. Finally, we thank David Nadziejka for his technical editing of this manuscript. The content is solely the responsibility of the authors.

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Correspondence to X Li.

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Meng, X., Vander Ark, A., Lee, P. et al. Myeloid-specific TGF-β signaling in bone promotes basic-FGF and breast cancer bone metastasis. Oncogene 35, 2370–2378 (2016) doi:10.1038/onc.2015.297

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