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Type: Journal article
Title: High mammographic density is associated with an increase in stromal collagen and immune cells within the mammary epithelium
Author: Huo, C.
Chew, G.
Hill, P.
Huang, D.
Ingman, W.
Hodson, L.
Brown, K.
Magenau, A.
Allam, A.
McGhee, E.
Timpson, P.
Henderson, M.
Thompson, E.
Britt, K.
Citation: Breast Cancer Research, 2015; 17(1):79-1-79-20
Publisher: BioMed Central
Issue Date: 2015
ISSN: 1465-542X
Statement of
Cecilia W. Huo, Grace Chew, Prue Hill, Dexing Huang, Wendy Ingman, Leigh Hodson, Kristy A. Brown, Astrid Magenau, Amr H. Allam, Ewan McGhee, Paul Timpson, Michael A. Henderson, Erik W. Thompson, and Kara Britt
Abstract: INTRODUCTION: Mammographic density (MD), after adjustment for a women's age and body mass index, is a strong and independent risk factor for breast cancer (BC). Although the BC risk attributable to increased MD is significant in healthy women, the biological basis of high mammographic density (HMD) causation and how it raises BC risk remain elusive. We assessed the histological and immunohistochemical differences between matched HMD and low mammographic density (LMD) breast tissues from healthy women to define which cell features may mediate the increased MD and MD-associated BC risk. METHODS: Tissues were obtained between 2008 and 2013 from 41 women undergoing prophylactic mastectomy because of their high BC risk profile. Tissue slices resected from the mastectomy specimens were X-rayed, then HMD and LMD regions were dissected based on radiological appearance. The histological composition, aromatase immunoreactivity, hormone receptor status and proliferation status were assessed, as were collagen amount and orientation, epithelial subsets and immune cell status. RESULTS: HMD tissue had a significantly greater proportion of stroma, collagen and epithelium, as well as less fat, than LMD tissue did. Second harmonic generation imaging demonstrated more organised stromal collagen in HMD tissues than in LMD tissues. There was significantly more aromatase immunoreactivity in both the stromal and glandular regions of HMD tissues than in those regions of LMD tissues, although no significant differences in levels of oestrogen receptor, progesterone receptor or Ki-67 expression were detected. The number of macrophages within the epithelium or stroma did not change; however, HMD stroma exhibited less CD206(+) alternatively activated macrophages. Epithelial cell maturation was not altered in HMD samples, and no evidence of epithelial-mesenchymal transition was seen; however, there was a significant increase in vimentin(+)/CD45(+) immune cells within the epithelial layer in HMD tissues. CONCLUSIONS: We confirmed increased proportions of stroma and epithelium, increased aromatase activity and no changes in hormone receptor or Ki-67 marker status in HMD tissue. The HMD region showed increased collagen deposition and organisation as well as decreased alternatively activated macrophages in the stroma. The HMD epithelium may be a site for local inflammation, as we observed a significant increase in CD45(+)/vimentin(+) immune cells in this area.
Keywords: Breast
Mammary Glands, Human
Stromal Cells
Breast Neoplasms
Risk Factors
Middle Aged
Epithelial-Mesenchymal Transition
Biomarkers, Tumor
Breast Density
Rights: © 2015 Huo et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
DOI: 10.1186/s13058-015-0592-1
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