title: Dietary polyphenols suppress elevated levels of proinflammatory mediators and aromatase in the mammary gland of obese mice.
abstract: In postmenopausal women, obesity is a risk factor for the development of hormone receptor-positive breast cancer driven by estrogen. After menopause, aromatization of androgen precursors in adipose tissue is a major synthetic source of estrogen. Recently, in mouse models and women, we identified an obesity-inflammation-aromatase axis. This obesity-induced inflammation is characterized by crown-like structures (CLS) consisting of dead adipocytes encircled by macrophages in breast white adipose tissue. CLS occur in association with NF-κB activation, elevated levels of proinflammatory mediators, and increased aromatase expression. Saturated fatty acids released from adipocytes have been linked to obesity-related white adipose tissue inflammation. Here we found that stearic acid, a prototypic saturated fatty acid, stimulated Akt-dependent activation of NF-κB resulting in increased levels of proinflammatory mediators [TNF-α, interleukin (IL)-1β, COX-2] in macrophages leading, in turn, to the induction of aromatase. Several polyphenols (resveratrol, curcumin, epigallocatechin gallate) blocked these inductive effects of stearic acid. Zyflamend, a widely used polyherbal preparation that contains numerous polyphenols, possessed similar suppressive effects. In a mouse model of obesity, treatment with Zyflamend suppressed levels of phospho-Akt, NF-κB binding activity, proinflammatory mediators, and aromatase in the mammary gland. Collectively, these results suggest that targeting the activation of NF-κB is a promising approach for reducing levels of proinflammatory mediators and aromatase in inflamed mouse mammary tissue. Further investigation in obese women is warranted.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, 525 East 68th St, Room F-206, New York, New York 10065, USA. ksubba@med.cornell.edu
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.forename: Erika
authors.initials: E
authors.lastname: Sue
authors.forename: Priya
authors.initials: P
authors.lastname: Bhardwaj
authors.forename: Baoheng
authors.initials: B
authors.lastname: Du
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.forename: Levy
authors.initials: L
authors.lastname: Kopelovich
authors.forename: Xi Kathy
authors.initials: XK
authors.lastname: Zhou
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D001141:Aromatase / Q000737:chemistry* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D004032:Diet; D004195:Disease Models, Animal; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042361:Mammary Glands, Human / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D059808:Polyphenols / Q000008:administration & dosage*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018836:Inflammation Mediators; D016328:NF-kappa B; D059808:Polyphenols; D012333:RNA, Messenger; D001141:Aromatase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt