Obesity Is Associated with Inflammation and Elevated Aromatase Expression in the Mouse Mammary Gland
- 1 March 2011
- journal article
- retracted article
- Published by American Association for Cancer Research (AACR) in Cancer Prevention Research
- Vol. 4 (3), 329-346
- https://doi.org/10.1158/1940-6207.capr-10-0381
Abstract
Elevated circulating estrogen levels are associated with increased risk of breast cancer in obese postmenopausal women. Following menopause, the biosynthesis of estrogens through CYP19 (aromatase)-mediated metabolism of androgen precursors occurs primarily in adipose tissue, and the resulting estrogens are then secreted into the systemic circulation. The potential links between obesity, inflammation, and aromatase expression are unknown. In both dietary and genetic models of obesity, we observed necrotic adipocytes surrounded by macrophages forming crown-like structures (CLS) in the mammary glands and visceral fat. The presence of CLS was associated with activation of NF-κB and increased levels of proinflammatory mediators (TNF-α, IL-1β, Cox-2), which were paralleled by elevated levels of aromatase expression and activity in the mammary gland and visceral fat of obese mice. Analyses of the stromal-vascular and adipocyte fractions of the mammary gland suggested that macrophage-derived proinflammatory mediators induced aromatase and estrogen-dependent gene expression (PR, pS2) in adipocytes. Saturated fatty acids, which have been linked to obesity-related inflammation, stimulated NF-κB activity in macrophages leading to increased levels of TNF-α, IL-1β, and Cox-2, each of which contributed to the induction of aromatase in preadipocytes. The discovery of the obesity → inflammation → aromatase axis in the mammary gland and visceral fat and its association with CLS may provide insight into mechanisms underlying the increased risk of hormone receptor-positive breast cancer in obese postmenopausal women, the reduced efficacy of aromatase inhibitors in the treatment of breast cancer in these women, and their generally worse outcomes. The presence of CLS may be a biomarker of increased breast cancer risk or poor prognosis. Cancer Prev Res; 4(3); 329–46. ©2011 AACR.Keywords
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This publication has 55 references indexed in Scilit:
- Inhibition of NF-kappa B activity in mammary epithelium increases tumor latency and decreases tumor burdenOncogene, 2010
- Analysis of estrogens in serum and plasma from postmenopausal women: Past present, and futureSteroids, 2010
- Macrophages, Inflammation, and Insulin ResistanceAnnual Review of Physiology, 2010
- Obesity and Cancer: The Role of Dysfunctional Adipose TissueCancer Epidemiology, Biomarkers & Prevention, 2009
- Toll-like receptor signaling links dietary fatty acids to the metabolic syndromeCurrent Opinion in Lipidology, 2009
- Obesity and Breast Cancer: The Estrogen ConnectionEndocrinology, 2009
- Differential susceptibility to obesity between male, female and ovariectomized female miceNutrition Journal, 2009
- Reduced Energy Expenditure and Increased Inflammation Are Early Events in the Development of Ovariectomy-Induced ObesityEndocrinology, 2009
- Effect of Tumor Necrosis Factor-α on Estrogen Metabolism and Endometrial Cells: Potential Physiological and Pathological RelevanceJournal of Clinical Endocrinology & Metabolism, 2009
- Overweight, obesity and cancer: epidemiological evidence and proposed mechanismsNature Reviews Cancer, 2004