Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo

Abstract

Inflammation is one of the hallmarks of carcinogenesis. High mammographic density has been associated with increased risk of breast cancer but the mechanisms behind are poorly understood. We evaluated whether breasts with different mammographic densities exhibited differences in the inflammatory microenvironment.Postmenopausal women attending the mammography-screening program were assessed having extreme dense, n D 20, or entirely fatty breasts (nondense), n D 19, on their regular mammograms. Thereafter, the women were invited for magnetic resonance imaging (MRI), microdialysis for the collection of extracellular molecules in situ and a core tissue biopsy for research purposes. On the MRI, lean tissue fraction (LTF) was calculated for a continuous measurement of breast density. LTF confirmed the selection from the mammograms and gave a continuous measurement of breast density. Microdialysis revealed significantly increased extracellular in vivo levels of IL-6, IL-8, vascular endothelial growth factor, and CCL5 in dense breast tissue as compared with nondense breasts. Moreover, the ratio IL-1Ra/IL-1b was decreased in dense breasts. No differences were found in levels of IL1b, IL-1Ra, CCL2, leptin, adiponectin, or leptin:adiponectin ratio between the two breast tissue types. Significant positive correlations between LTF and the pro-inflammatory cytokines as well as between the cytokines were detected. Stainings of the core biopsies exhibited increased levels of immune cells in dense breast tissue.Our data show that dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment and, if confirmed in a larger cohort, suggests novel targets for prevention therapies for women with dense breast tissue.

The effects of flaxseed and tamoxifen on the inflammatory microenvironment in normal breast tissue and in breast cancer

“…Although the pathogenesis is not fully understood, it has been suggested that increased inflammation may be one contributing factor, but the evidence is inconsistent; while one study showed no association between MD and the expression of inflammatory markers, another study showed an association between high MD and the expression of IL-6 in all women and, an association with the expression of TNF, CRP and IL-8 in premenopausal women (32,33). This corroborates an in vivo study of inflammatory mediators in the microenvironment in healthy postmenopausal women were we found significant associations between reduced IL-1Ra/IL-1β ratio, increased levels of IL-6, IL-8, VEGF and CCL2 in breast tissue with extremely high MD compared to breast tissue with low MD (34). We have also shown that out of 32 pro-inflammatory mediators assessed, 26 proteins exhibited similar profiles in breast cancer and dense breast tissue suggesting a pro-inflammatory microenvironment as a possible initiator of malignant transformation in dense breast tissue (35).…”

“…Studies have investigated the association between inflammatory markers in breast tissue sections and MD with inconsistent results (32,33). However, we have shown that postmenopausal women with extremely high MD have a more pro-inflammatory microenvironment compared to women with low MD which could contribute to a higher risk of developing breast cancer (34). Furthermore, we have also compared postmenopausal women with dense breast tissue to women with breast cancer and found that 26 of 32 inflammatory mediators showed similar profile (35).…”

Downregulation of tumor suppressive microRNAs in vivo in dense breast tissue of postmenopausal women

“…Thus, a more sophisticated biological characterization of dense breast tissue is key for the development of preventive measures of breast cancer associated with less toxicity compared to anti-estrogens. We have recently shown that dense breast tissue is associated with a pro-inflammatory microenvironment [ 10 ].…”

Fat-Referenced MRI: Quanitaive MRI for Tissue Characterizaion and Volume Measurement

“…In the second study, we saw that the MRI measured breast density correlated with inflammation markers (indicating increased cancer 7. D risk) [75]. This application is interesting, as MRI is not uncommon when screening high risk individuals, and the RFC-image analysis is next to trivial.…”

“…This evaluation has however become outdated as both reference methods have been upgraded, and the water-fat swaps seen in paper I have become less common. The PSR algorithm has also been successfully used in a range of studies [32,[68][69][70][71][72][73][74][75][76][77][78]. These studies did not directly evaluate the performance of PSR.…”