title: Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production.
abstract: Obesity is associated with a worse breast cancer prognosis, particularly in estrogen receptor alpha (ERα) positive, postmenopausal patients. We hypothesized that this is mediated in part by an elevation in breast cancer cell cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production that results in greater local pre-adipocyte aromatase expression. We utilized an in vitro model of the obese patient's tumor microenvironment in which cultured MCF-7 breast cancer cells and pre-adipocytes were exposed to pooled serum from obese (OB; BMI ≥ 30.0 kg/m(2)) or normal weight (N; BMI 18.5-24.9 kg/m(2)) postmenopausal women. Exposure to OB versus N sera significantly increased MCF-7 cell COX-2 expression and PGE2 production. Pre-adipocyte aromatase expression was 89 % greater following culture in conditioned media (CM) from MCF-7 cells exposed to OB versus N sera (OB-CM and N-CM, respectively), a difference nullified by MCF-7 cell treatment with the COX-2 inhibitor celecoxib. Previous analysis of the sera revealed significantly higher interleukin-6 (IL-6) concentrations in the OB versus N samples. Depletion of IL-6 from the sera neutralized the difference in pre-adipocyte aromatase expression stimulated by OB-CM versus N-CM. Finally, CM from pre-adipocyte/MCF-7 cell co-cultures exposed to OB sera stimulated greater MCF-7 and T47D breast cancer cell ERα activity and proliferation in comparison to N sera. This study indicates that obesity-associated systemic IL-6 indirectly enhances pre-adipocyte aromatase expression via increased breast cancer cell PGE2 production. Investigation regarding the efficacy of a COX-2 inhibitor/aromatase inhibitor combination therapy in the obese postmenopausal patient population is warranted.
authors.affiliation: Department of Nutrition, University of North Carolina at Chapel Hill, 135 Dauer Drive, McGavran-Greenberg Hall, Chapel Hill, NC, 27599, USA, laurawbowers@gmail.com.
authors.forename: Laura W
authors.initials: LW
authors.lastname: Bowers
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Brenner
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Hursting
authors.forename: Rajeshwar R
authors.initials: RR
authors.lastname: Tekmal
authors.forename: Linda A
authors.initials: LA
authors.lastname: deGraffenried
mesh_terms: D017667:Adipocytes / Q000201:enzymology; D001141:Aromatase / Q000096:biosynthesis*; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000150:complications / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000096:biosynthesis; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage; D015232:Dinoprostone / Q000096:biosynthesis*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics* / Q000276:immunology; D061986:MCF-7 Cells; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000473:pathology; D000093242:Interleukin-6 Inhibitors
chemical_list: D001141:Aromatase; D047072:Aromatase Inhibitors; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D015232:Dinoprostone; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors