title: Estrogen Protects against Obesity-Induced Mammary Gland Inflammation in Mice.
abstract: Obesity is a risk factor for the development of hormone receptor (HR)-positive breast cancer in postmenopausal women. Obesity causes subclinical inflammation in white adipose tissue (WAT), characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase. Previously, we demonstrated CLS and elevated levels of proinflammatory mediators and aromatase in the mammary glands of obese mice and breast tissue of obese women. Here, we tested the hypothesis that supplemental estrogen could prevent or reverse WAT inflammation (WATi) and related molecular changes in the mammary gland. C57BL/6J mice were ovariectomized (OVX) to simulate the postmenopausal state. Supplementation with 17β-estradiol (E2) protected against high fat diet (HFD)-induced weight gain and mammary glands WATi. Expression of proinflammatory mediators (Cox-2, TNFα, IL1β) and aromatase were also reduced in the mammary glands of mice that received supplemental E2. Next, to determine whether E2 supplementation can reverse WATi, obese OVX mice were treated with E2 or placebo and then continued on HFD. E2 supplementation induced weight loss, reversed mammary gland inflammation, and downregulated expression of proinflammatory mediators and aromatase. Finally, we determined whether the protective effects of E2 were mediated by estrogen receptor-α (ERα). Knocking out ERα in ovary intact mice fed a HFD led to weight gain, WATi and elevated levels of proinflammatory mediators and aromatase mimicking the effects of OVX. Taken together, our findings indicate that estrogen via ERα protects against weight gain, WATi and associated increases in proinflammatory mediators and aromatase in the mammary gland.
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Priya
authors.initials: P
authors.lastname: Bhardwaj
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Baoheng
authors.initials: B
authors.lastname: Du
authors.affiliation: Department of Healthcare Policy and Research, Weill Cornell Medical College, New York, New York.
authors.forename: Xi Kathy
authors.initials: XK
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Erika
authors.initials: E
authors.lastname: Sue
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Dilip
authors.initials: D
authors.lastname: Giri
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Harbus
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Domenick J
authors.initials: DJ
authors.lastname: Falcone
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Clifford A
authors.initials: CA
authors.lastname: Hudis
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Kotha
authors.initials: K
authors.lastname: Subbaramaiah
authors.affiliation: Department of Medicine, Weill Cornell Medical College, New York, New York. ajdannen@med.cornell.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Dannenberg
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004967:Estrogens / Q000627:therapeutic use*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000187:drug effects* / Q000473:pathology; D008413:Mastitis / Q000209:etiology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000503:physiopathology; D010052:Ovariectomy; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015430:Weight Gain / Q000187:drug effects
chemical_list: D004967:Estrogens; D018836:Inflammation Mediators; D012333:RNA, Messenger