Menopause is a determinant of breast adipose inflammation

Abstract

Chronic inflammation is recognized as a risk factor for the development of several malignancies. Local white adipose tissue (WAT) inflammation, defined by the presence of dead or dying adipocytes encircled by macrophages that form crown-like structures (CLS), occurs in the breasts (CLS-B) of most overweight and obese women. Previously, we showed that the presence of CLS-B is associated with elevated tissue levels of proinflammatory mediators and aromatase, the rate-limiting enzyme for estrogen biosynthesis. The associated increased levels of aromatase in the breast provide a plausible mechanistic link between WAT inflammation and estrogen-dependent breast cancers. Thus, breast WAT inflammation could be relevant for explaining the high incidence of estrogen-dependent tumors with aging despite diminished circulating estrogen levels after menopause. To explore this possibility, we determined whether menopause in addition to body mass index (BMI) is associated with breast WAT inflammation among 237 prospectively enrolled women. The presence of CLS-B and its severity (CLS-B/cm(2)) as indicators of WAT inflammation correlated with menopausal status (P = 0.008 and P < 0.001) and BMI (P < 0.001 for both). In multivariable analyses adjusted for BMI, the postmenopausal state was independently associated with the presence (P = 0.03) and severity of breast WAT inflammation (P = 0.01). Mean adipocyte size increased in association with CLS-B (P < 0.001). Our findings demonstrate that breast WAT inflammation, which is associated with elevated aromatase levels, is increased in association with the postmenopausal state independent of BMI. Breast WAT inflammation, a process that can potentially be targeted, may help to explain the high incidence of estrogen-dependent tumors in postmenopausal women.

Figure 1. CLS-B are more common and more severe in obese and postmenopausal women

A. H&E stained slide showing CLS-B (200×). B. Immunohistochemical staining of CD68 of same lesion shown in panel A (200×). C. Prevalence of CLS-B is higher in overweight and obese patients. D. Prevalence of CLS-B is higher in postmenopausal women. E. Overweight and obese postmenopausal women have the highest prevalence of CLS-B. F. Overweight and obese postmenopausal women have the highest prevalence of severe breast WAT inflammation (CLS-B/cm² >0.38). Difference in prevalence of CLS-B (C, D, E) or prevalence of severe breast WAT inflammation (F) across groups were assessed using Fisher’s exact test.

Figure 2. Adipocyte size correlates with BMI and WAT inflammation, and is larger in postmenopausal and obese women

A. A moderate correlation was observed between mean adipocyte size and BMI (ρ=0.63, P<0.001, Pearson’s method). B. Patients with CLS-B have larger mean adipocyte size in the breast (P<0.001, t-test). C. Mean adipocyte size increases with more severe breast WAT inflammation (P<0.001, ANOVA). D. Mean adipocyte size is larger in postmenopausal women (P=0.002, t-test). E. Mean adipocyte size is larger in overweight and obese postmenopausal women (P<0.001, ANOVA).