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. 2017 May 1;102(5):1692-1701.
doi: 10.1210/jc.2016-3606.

Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers

Kristy A Brown  1 , Neil M Iyengar  2   3 , Xi Kathy Zhou  4 , Ayca Gucalp  2   3 , Kotha Subbaramaiah  3 , Hanhan Wang  4 , Dilip D Giri  5 , Monica Morrow  6 , Domenick J Falcone  7 , Nils K Wendel  3 , Lisle A Winston  3 , Michael Pollak  8 , Anneloor Dierickx  3 , Clifford A Hudis  2   3 , Andrew J Dannenberg  3
Affiliations

Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers

Kristy A Brown et al. J Clin Endocrinol Metab. .

Abstract

Context: Most estrogen-dependent breast cancers occur after menopause, despite low levels of circulating estrogens. Breast expression of the estrogen-biosynthetic enzyme, aromatase, is proposed to drive breast cancer development after menopause. However, the effects of menopause on breast aromatase expression are unknown.

Objective: To determine the effect of menopause on breast aromatase expression in relation to body mass index (BMI), white adipose tissue inflammation (WATi), and systemic markers of metabolic dysfunction.

Design, setting, and participants: Cross-sectional study of 102 premenopausal (age 27 to 56) and 59 postmenopausal (age 45 to 74) women who underwent mastectomy for breast cancer treatment/prevention.

Outcome: Breast tissue was assessed for the presence of crown-like structures and the expression and activity of aromatase. Systemic markers examined include interleukin (IL)-6, insulin, glucose, leptin, adiponectin, high-sensitivity C-reactive protein (hsCRP), cholesterol, and triglycerides. Multivariable analysis was performed for aromatase messenger RNA (mRNA) in relation to BMI, WATi, and blood markers.

Results: Postmenopausal women had higher BMI and more breast WATi than premenopausal women. Fasting levels of IL-6, glucose, leptin, hsCRP, and homeostatic model assessment 2 insulin resistance score were higher in the postmenopausal group. BMI was positively correlated with aromatase mRNA in both pre- and postmenopausal women. Aromatase levels were higher in breast tissue of postmenopausal women, with levels being higher in inflamed vs noninflamed, independent of BMI. Adipocyte diameter and levels of leptin, hsCRP, adiponectin, and high-density lipoprotein cholesterol were more strongly correlated with aromatase in postmenopausal than premenopausal women.

Conclusions: Elevated aromatase in the setting of adipose dysfunction provides a possible mechanism for the higher incidence of hormone-dependent breast cancer in obese women after menopause.

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Figures

Figure 1.
Figure 1.
Effect of menopausal status on breast aromatase in relation to BMI. Breast levels of (a) aromatase mRNA and (b) activity are higher in postmenopausal compared with premenopausal women. (c) Aromatase transcript expression is positively correlated with BMI in pre- (black; ρ = 0.23; P = 0.02) and postmenopausal (red; ρ = 0.4; P = 0.002) women. (d) Menopause and overweight/obesity are associated with elevated levels of aromatase mRNA. Transcript expression was assessed in n = 161 (102 premenopausal, 59 postmenopausal), whereas aromatase activity was measured in n = 6/group.
Figure 2.
Figure 2.
Impact of menopausal status on breast adipocyte diameter and WATi, and their association with aromatase. (a) Postmenopausal women have higher median breast adipocyte diameters than premenopausal women. (b) Aromatase mRNA levels are positively correlated with adipocyte diameters in postmenopausal (red; ρ = 0.5; P < 0.001), but not premenopausal women (black; ρ = 0.11; P = 0.29). (c) Representative images of WATi in breast. Hematoxylin and eosin (left) and CD68-stained (right) CLS-B (arrows). (d) The proportion of CLS-B+ cases is higher in postmenopausal compared with premenopausal women. (e) Aromatase is also positively correlated with CLS-B/cm2 in both pre (black; ρ = 0.21; P = 0.04) and postmenopausal (red; ρ = 0.57; P < 0.001) women. The strength of the association is stronger in postmenopausal women compared with premenopausal women.
Figure 3.
Figure 3.
Effect of menopause on correlations between aromatase and markers of metabolic function. Aromatase mRNA is positively correlated with (a) leptin (ρ = 0.38; P = 0.003) and (b) hsCRP (ρ = 0.46; P < 0.001) in postmenopausal women (red), but not premenopausal women (black). An inverse correlation is observed between aromatase transcript expression and (c) adiponectin (ρ = 0.4; P = 0.002) and (d) HDL cholesterol (ρ = 0.49; P < 0.001) levels in the postmenopausal (red), but not the premenopausal (black) group.
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