Immune Regulation of Mammary Fibroblasts and the Impact of Mammographic Density.

Maddison Archer,David Walsh,Kara L Britt,Andreas Evdokiou,Pallave Dasari,Wendy V Ingman

doi:10.3390/jcm11030799

Abstract

Mammographic density is associated with a 4–6-fold increase in breast cancer risk independent of age and BMI. High mammographic density is characterized by breast tissue with high proportions of stroma comprised of fibroblasts, collagen, and immune cells. This study sought to investigate whether stromal fibroblasts from high mammographic density breast tissue contributes to increased extracellular matrix deposition and pro-tumorigenic signaling. Mammary fibroblasts were isolated from women with high and low mammographic density and exposed to immune factors myeloperoxidase (MPO), eosinophil peroxidase (EPO), transforming growth factor beta 1 (TGFB1) and tumour necrosis factor alpha (TNFA) for 72 h and profiled for expression of cancer-associated fibroblast and extracellular matrix regulation markers. No differences in gene expression profiles or collagen production were observed between fibroblasts with high or low mammographic density, and they did not have a differential response to immune mediators. MPO and EPO significantly increased the production of collagen 1. TGFB and TNFA induced variable changes in gene expression. Fibroblasts cultured in vitro from women with high mammographic density do not appear to be inherently different to those from women with low mammographic density. The function of fibroblasts in mammographic density-associated breast cancer risk is likely to be regulated by immune signals from surrounding cells in the microenvironment.

Highlights

Histological studies have reported that the key features of high mammographic density (MD) breast tissue are a higher abundance of stroma and greater deposition of collagen compared to low MD tissue [1,2]
This study aims to investigate the fibrotic activity of fibroblasts derived from high and low MD breast tissue by analysing the expression of genes involved in extracellular matrixes (ECM) regulation including MMP1, MMP3, Connective tissue growth factor (CTGF), lysyl oxidase (LOX), FBN, COL1A1 and COL4A5 as well as production of soluble collagen 1 and insoluble collagen
Our studies found that mammary fibroblasts treated with transforming growth factor beta 1 (TGFB1) displayed increased mRNA expression of genes involved in ECM regulation such as MMP3, CTGF and LOX, as well as alterations in collagen production

Summary

Introduction

Histological studies have reported that the key features of high mammographic density (MD) breast tissue are a higher abundance of stroma and greater deposition of collagen compared to low MD tissue [1,2]. High MD breast tissue can be considered to resemble tissues with fibrosis, which are characterised by excessive deposition of collagen and extracellular matrixes (ECM) [3]. The most abundant cell type in the mammary stroma are fibroblasts, which are the key cell type responsible for fibrotic activities such as regulation of the synthesis and turnover of collagen and extracellular matrix (ECM). High abundance of collagen associated with fibrosis increases breast cancer risk in a transgenic mouse model [6] and this suggests that fibroblast-mediated fibrosis could be a key driver of MD. CAFs can promote the transformation of with regard to jurisdictional claims in published maps and institutional affiliations

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