Abstract

BackgroundMacrophages 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.MethodsTransgenic 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.ResultsOverexpression 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.ConclusionsConstitutive 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.

Highlights

  • Macrophages play diverse roles in mammary gland development and breast cancer

  • In order to exert this wide range of effects in healthy development and cancer susceptibility in the mammary gland, macrophages respond to a variety of different signals in their local microenvironment, including cytokines emanating from other cell types, and components of the extracellular matrix

  • To investigate the effect of CC-chemokine ligand 2 (CCL2) in mammary gland development and function, we developed a transgenic mouse model mammary tumour virus promoter (Mmtv)-Ccl2, whereby CCL2 is constitutively expressed by the mammary epithelium

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Summary

Introduction

Macrophages play diverse roles in mammary gland development and breast cancer. Macrophages are a major component of the stroma, and have the capacity to direct a diverse range of biological processes necessary for mammary gland development, including cell proliferation, differentiation, phagocytosis, and tissue remodelling [1,2,3,4,5,6]. In addition to roles in healthy development, macrophages may affect cancer susceptibility [7, 8]. In order to exert this wide range of effects in healthy development and cancer susceptibility in the mammary gland, macrophages respond to a variety of different signals in their local microenvironment, including cytokines emanating from other cell types, and components of the extracellular matrix

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