Abstract
IntroductionMammographic 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.MethodsTissues 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.ResultsHMD 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.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-015-0592-1) contains supplementary material, which is available to authorized users.
Highlights
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)
The study cohort A total of 48 high-risk women were included in this study; of these, 4 women had suspicious ductal carcinoma in situ (DCIS) based on specimen radiographs, and 3 women had tissue samples with a homogeneous radiological appearance
In a small case–control study on postmenopausal women who received hormone therapy (HT) (28 receiving HT vs. 28 not receiving HT at the time of BC diagnosis), researchers found that high mammographic density (HMD) correlated with increased Ki-67 expression in ducts and lobules for both groups, their data appear to be the only published data supporting a positive relationship between HMD and Ki-67, a result that may be mediated by the use of hormone therapy in those postmenopausal patients [46]
Summary
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). 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. Important risk factors for breast cancer (BC) are increasing age, genetic mutations, family history or personal history of BC and mammographic density (MD), which refers to the extent of opaque appearance on a mammogram [1]. The link between high MD and BC risk is in the public domain Advocacy groups such as Are You Dense? As the biological basis of MD is not understood, viable preventative and/or therapeutic targets aimed at reducing MD-associated BC risk have yet to be developed
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