Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers
J Clin Endocrinol Metab, May
Menopause Is a Determinant of Breast Aromatase Expression and Its Associations With BMI, Inflammation, and Systemic Markers
Kristy A. Brown 0 8
Neil M. Iyengar 1 4 8
Xi Kathy Zhou 5 8
Ayca Gucalp 1 4 8
Kotha Subbaramaiah 4 8
Hanhan Wang 5 8
Dilip D. Giri 2 8
Monica Morrow 3 8
Domenick J. Falcone 6 8
Nils K. Wendel 4 8
Lisle A. Winston 4 8
Michael Pollak 7 8
Anneloor Dierickx 4 8
Clifford A. Hudis 1 4 8
Andrew J. Dannenberg 4 8
0 Metabolism and Cancer Laboratory, Centre for Cancer Research, Hudson Institute of Medical Research, and Monash University , Clayton, Victoria 3168 , Australia
1 Department of Medicine, Memorial Sloan Kettering Cancer Center , New York, New York 10065 , USA
2 Department of Pathology, Memorial Sloan Kettering Cancer Center , New York, New York 10065 , USA
3 Department of Surgery, Memorial Sloan Kettering Cancer Center , New York, New York 10065 , USA
4 Department of Medicine, Weill Cornell Medical College , New York, New York 10065 , USA
5 Department of Healthcare Policy and Research, Weill Cornell Medical College , New York, New York 10065 , USA
6 Department of Pathology and Laboratory Medicine, Weill Cornell Medical College , New York, New York 10065 , USA
7 Departments of Medicine and Oncology, McGill University , Montreal, Quebec , Canada H3T 1E2
8 structures of the breast; HOMA2-IR , homeostatic model assessment 2 insulin resistance; hsCRP, high-sensitivity C-reactive protein; IL, interleukin; mRNA, messenger RNA; MSKCC , Memorial Sloan Kettering Cancer Center; PCR , polymerase chain reaction; WAT, white adipose tissue; WATi, white adipose tissue inflammation
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. (J Clin Endocrinol Metab 102: 1692-1701, 2017)
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Mhormone levels, which contribute to physical and
enopause is associated with significant changes in
biological consequences that impact disease. For
example, the menopausal transition has been associated with
weight gain and central adiposity, elevated levels of
systemic markers of inflammation, and metabolic
dysfunction including C-reactive protein (CRP), interleukin
(IL)-6, tumor necrosis factor-a, and leptin and increased
incidence of metabolic syndrome and cardiovascular
disease (
1?4
). Many cancers, including breast cancer, also
occur more frequently after menopause. Despite low
levels of circulating estrogens (5), the majority of breast
cancers that occur after menopause are estrogen
dependent (
6
), and the risk of breast cancer in these women
is increased with obesity and metabolic syndrome (
7
).
Aromatase is the enzyme that catalyzes the final and
key step in estrogen biosynthesis. Considering the low
concentrations of circulating estrogens after menopause,
it has been proposed that breast-derived estrogens are key
drivers of breast cancer growth and that established
tumors have the capacity to further increase the local
production of estrogens (
8
). Consistent with this
hypothesis, aromatase levels and activity have been reported
to be highest in the breast quad (...truncated)