Inflammation of mammary adipose tissue occurs in overweight and obese patients exhibiting early-stage breast cancer

Abstract

Growing evidence indicates that adiposity is associated with breast cancer risk and negatively affects breast cancer recurrence and survival, a paracrine role of mammary adipose tissue being very likely in this process. In contrast to other adipose depots, occurrence of a sub-inflammatory state of mammary adipose tissue defined by dying adipocytes surrounded by macrophages forming crown-like structures in overweight and obese subjects, remains only partially described. In a general population of breast cancer patients (107 patients) mostly undergoing breast-conserving surgery, we found a positive association between patient's body composition, breast adipocytes size, and presence of crown-like structures in mammary adipose tissue close to the tumor. Overweight (BMI: 25.0-29.9 kg/m²) and obese (BMI ≥ 30.0 kg/m²) patients have 3.2 and 6.9 times higher odds ratio of crown-like structures respectively, compared with normal weight patients. The relatively small increase in adipocyte size in crown-like structures positive vs. negative patients suggests that mammary adipose tissue inflammation might occur early during hypertrophy. Our results further highlight that body mass index is an adequate predictor of the presence of crown-like structures in mammary adipose tissue among postmenopausal women, whereas in premenopausal women truncal fat percentage might be more predictive, suggesting that mammary adipose tissue inflammation is more likely to occur in patients exhibiting visceral obesity. Finally, the presence of crown-like structures was positively associated with systemic markers such as the Triglyceride/High-density lipoprotein-cholesterol ratio serum C-reactive protein and glucose/(HbA1c) glycated Haemoglobin. These compelling results demonstrate that excess adiposity, even in overweight patients, is associated with mammary adipose tissue inflammation, an event that could contribute to breast cancer development and progression.

Fig. 1

CLS are found in MAT and macrophages constituting CLS are pro-inflammatory. a Photomicrographs of CD68 stained tumor slides showing macrophages in isolated ring-like formations surrounding dying or dead adipocytes (indicated by red arrows). Density of CLS in breast fat tissue away from tumor border was scored as number of CLS divided by area of fat tissue. a ×25 magnification, red arrow: CLS, black arrow: tumor; b ×150 magnification; c ×300 magnification of CLS detected in the MAT of an obese patient (BMI = 30 kg/m²) exhibiting hypertrophied adipocyte (mean adipocyte diameter 82.09 µm). b IL6 expression was evaluated in 5 samples exhibiting CLS obtained from overweight patients (BMI from 26.4 to 29.5 kg/m²) (Samples 1 to 5) (×200 magnification). The figures below (numbered 1’ to 5’) show two-fold-magnified views of selected areas indicated by insets. Similar experiments were performed in samples without CLS obtained from normal weight patients (BMI from 17.9 to 24.8 kg/m²) numbered (6 to 10), with two fold-magnified views of selected areas (6’ to 10’)

Fig. 2

Distribution of CLS density (top panel) or adipocyte diameter (bottom panel), stratified in lean vs. overweight/obese patients, as measured either by BMI (left panel) or WHR (right panel). The P-values are obtained from tests of equal medians

Fig. 3

Existence of a relationship between CLS density and adipocyte size. a Scatter plot and linear relationship of CLS density and adipocyte diameter. The P-value is obtained from a test of no linear association. b Box plot that shows the distribution of adipocytes diameter, stratified by presence of CLS

Fig. 4

Scatterplots and linear relationships of anthropometric measures (y-axis) and adipocyte diameter (x-axis, left panel) or CLS density (x-axis, right panel). The P-values are obtained from tests of no linear association