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Ethanol promotes mammary tumor growth and angiogenesis: the involvement of chemoattractant factor MCP-1

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Abstract

Alcohol consumption is a risk factor for breast cancer in humans. Experimental studies indicate that alcohol exposure promotes malignant progression of mammary tumors. However, the underlying cellular and molecular mechanisms remain unclear. Alcohol induces a pro-inflammatory response by modulating the expression of cytokines and chemokines. Monocyte chemoattractant protein-1 (MCP-1), also known as chemokine (C–C motif) ligand 2, is a pro-inflammatory chemokine implicated in breast cancer development/malignancy. We investigated the role of MCP-1 in alcohol-promoted mammary tumor progression. Using a xenograft model, we demonstrated that alcohol increased tumor angiogenesis and promoted growth/metastasis of breast cancer cells in C57BL/6 mice. Alcohol up-regulated the expression of MCP-1 and its receptor CCR2 in breast cancer cells in vitro and in vivo. Using a three-dimensional tumor/endothelial cell co-culture system, we demonstrated MCP-1 regulated tumor/endothelial cell interaction and promoted tumor angiogenesis. More importantly, MCP-1 mediated alcohol-promoted angiogenesis; an antagonist of the MCP-1 receptor CCR2 significantly inhibited alcohol-stimulated tumor angiogenesis. The CCR2 antagonist abolished ethanol-stimulated growth of mammary tumors in mice. We further demonstrated that MCP-1 enhanced the migration, but not the proliferation of endothelial cells as well as breast cancer cells. These results suggest that MCP-1 plays an important role in ethanol-stimulated tumor angiogenesis and tumor progression.

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Abbreviations

AMVD:

Average microvessel density

CCL2:

Chemokine (C–C motif) ligand 2

CCR2:

CC chemokine receptor 2

CCR2A:

CCR2 antagonist

MCP-1:

Monocyte chemoattractant protein-1

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Acknowledgment

This research is supported by grants from National Institute of Health (AA017226 and AA015407).

Conflict of interest

The authors declare that they have no conflict of interests.

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Authors and Affiliations

  1. Department of Internal Medicine, University of Kentucky College of Medicine, 130 Health Sciences Research Building, 1095 Veterans Drive, Lexington, KY, 40536, USA

    Siying Wang, Mei Xu, Kimberly A. Bower, Jacqueline A. Frank, Gang Chen & Jia Luo

  2. Pathophysiological Department, School of Basic Medicine, Anhui Medical University, 69 Mei Shan Road, Hefei, 230032, Anhui, China

    Siying Wang, Feifei Li & Yanmin Lu

  3. Graduate Center for Toxicology, University of Kentucky, Lexington, KY, 40536, USA

    Xin Wang, Zhuo Zhang & Xianglin Shi

  4. Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, 200031, China

    Zunji Ke

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  1. Siying Wang
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  2. Mei Xu
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  3. Feifei Li
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  4. Xin Wang
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Correspondence to Siying Wang or Jia Luo.

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Wang, S., Xu, M., Li, F. et al. Ethanol promotes mammary tumor growth and angiogenesis: the involvement of chemoattractant factor MCP-1. Breast Cancer Res Treat 133, 1037–1048 (2012). https://doi.org/10.1007/s10549-011-1902-7

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  • DOI: https://doi.org/10.1007/s10549-011-1902-7

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