CCL2-driven inflammation increases mammary gland stromal density and cancer susceptibility in a transgenic mouse model.

Xuan Sun, Danielle J Glynn, Leigh J Hodson, Cecilia Huo, Kara Britt, Erik Thompson, Andreas Evdokiou, Jeffrey Pollard, Sarah A Robertson, Wendy V Ingman

Research output: Contribution to journalArticlepeer-review

Abstract

Background
Macrophages play diverse roles in mammary gland development and breast cancer. Chemokine (C-C motif) 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.
Methods
Transgenic mice were generated wherein CCL2 is driven by the mammary epithelial cell-specific 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, as well as mRNA encoding matrix remodelling enzymes. Another cohort of control and transgenic mice received carcinogen DMBA and tumour development was monitored weekly. CCL2 protein was also quantified in paired samples of high and low mammographic density human breast tissue.
Results
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 LOX and TIMP3 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. Conclusions
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.
Original languageEnglish
JournalBreast Cancer Research
Early online date11 Jan 2017
DOIs
Publication statusE-pub ahead of print - 11 Jan 2017

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