Excess body fat and sedentary behavior are associated with increased breast cancer risk and mortality, including in normal weight women. To investigate underlying mechanisms, we examined whether adiposity and exercise impact the breast microenvironment (e.g., inflammation and aromatase expression) and circulating metabo-inflammatory factors. In a cross-sectional cohort study, breast white adipose tissue (WAT) and blood were collected from 100 women undergoing mastectomy for breast cancer risk reduction or treatment. Self-reported exercise behavior, body composition measured by dual-energy x-ray absorptiometry (DXA), and waist:hip ratio were obtained prior to surgery. Breast WAT inflammation (B-WATi) was assessed by immunohistochemistry and aromatase expression was assessed by quantitative PCR. Metabolic and inflammatory blood biomarkers that are predictive of breast cancer risk and progression were measured. B-WATi was present in 56/100 patients and was associated with older age, elevated BMI, postmenopausal status, decreased exercise, hypertension and dyslipidemia (Ps<0.001). Total body fat and trunk fat correlated with B-WATi and breast aromatase levels (Ps<0.001). Circulating C-reactive protein, interleukin-6, insulin and leptin positively correlated with body fat and breast

Increased trunk fat is associated with an elevated risk of breast cancer in normal-weight postmenopausal women. The main objective of this study was to determine whether levels of trunk fat are associated with changes in breast gene expression in normal-weight women. Non-tumorous breast tissue was collected from 32 normal BMI women who underwent mastectomy for breast cancer risk reduction or treatment. Body composition was measured by dual-energy x-ray absorptiometry. High levels of trunk fat were associated with a large number of differentially expressed genes and changes in multiple pathways and processes potentially linked to breast cancer pathogenesis. High levels of trunk fat were also associated with an elevated immune score and increased levels of leptin, CCL2, VEGF-C, IL6, and aromatase. Collectively, these results help to explain why high levels of trunk fat are associated with an increased risk of breast cancer in normal BMI women.

Obesity is associated with an increased risk of breast cancer in post-menopausal women and decreased risk in pre-menopausal women. Conversely, in BRCA1/2 mutation carriers, pre-menopausal obesity is associated with early-onset breast cancer. Here we show that obese, pre-menopausal BRCA1/2 mutation carriers have increased levels of aromatase and inflammation in the breast, as occurs in post-menopausal women. In a prospective cohort study of 141 women with germline BRCA1 (n = 74) or BRCA2 (n = 67) mutations, leptin, and aromatase expression were higher in the breast tissue of obese versus lean individuals (P < 0.05). Obesity was associated with breast white adipose tissue inflammation, which correlated with breast aromatase levels (P < 0.01). Circulating C-reactive protein, interleukin-6, and leptin positively correlated with body mass index and breast aromatase levels, whereas negative correlations were observed for adiponectin and sex hormone-binding globulin (P < 0.05). These findings could help explain the increased risk of early-onset breast cancer in obese BRCA1/2 mutation carriers.

<p>Supplementary Tables S1, S2, and S3</p>

<p>Supplementary Tables S1, S2, and S3</p>