Please use this identifier to cite or link to this item: http://hdl.handle.net/2440/106226
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Type: Journal article
Title: CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model
Author: Sun, X.
Glynn, D.
Hodson, L.
Huo, C.
Britt, K.
Thompson, E.
Woolford, L.
Evdokiou, A.
Pollard, J.
Robertson, S.
Ingman, W.
Citation: Breast Cancer Research, 2017; 19(1):4-1-4-15
Publisher: BioMed Central
Issue Date: 2017
ISSN: 1465-5411
1465-542X
Statement of
Responsibility: 
Xuan Sun, Danielle J. Glynn, Leigh J. Hodson, Cecilia Huo, Kara Britt, Erik W. Thompson, Lucy Woolford, Andreas Evdokiou, Jeffrey W. Pollard, Sarah A. Robertson and Wendy V. Ingman
Abstract: Macrophages play diverse roles in mammary gland development and breast cancer. CC-chemokine ligand 2 (CCL2) is an inflammatory cytokine that recruits macrophages to sites of injury. Although CCL2 has been detected in human and mouse mammary epithelium, its role in regulating mammary gland development and cancer risk has not been explored.Transgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific mouse mammary tumour virus 206 (MMTV) promoter. Estrous cycles were tracked in adult transgenic and non-transgenic FVB mice, and mammary glands collected at the four different stages of the cycle. Dissected mammary glands were assessed for cyclical morphological changes, proliferation and apoptosis of epithelium, macrophage abundance and collagen deposition, and mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen 7,12-Dimethylbenz(a)anthracene (DMBA) and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of human breast tissue with high and low mammographic density.Overexpression of CCL2 in the mammary epithelium resulted in an increased number of macrophages, increased density of stroma and collagen and elevated mRNA encoding matrix remodelling enzymes lysyl oxidase (LOX) and tissue inhibitor of matrix metalloproteinases (TIMP)3 compared to non-transgenic controls. Transgenic mice also exhibited increased susceptibility to development of DMBA-induced mammary tumours. In a paired sample cohort of human breast tissue, abundance of epithelial-cell-associated CCL2 was higher in breast tissue of high mammographic density compared to tissue of low mammographic density.Constitutive expression of CCL2 by the mouse mammary epithelium induces a state of low level chronic inflammation that increases stromal density and elevates cancer risk. We propose that CCL2-driven inflammation contributes to the increased risk of breast cancer observed in women with high mammographic density.
Keywords: Chemokine (C-C motif) ligand 2; Development; Macrophage; Mammary gland; Mammographic density; Mouse model
Rights: © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
RMID: 0030062374
DOI: 10.1186/s13058-016-0796-z
Appears in Collections:Medicine publications

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