Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production

Breast Cancer Res Treat. 2015 Jan;149(1):49-57. doi: 10.1007/s10549-014-3223-0. Epub 2014 Dec 5.


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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipocytes / enzymology
  • Aromatase / biosynthesis*
  • Aromatase Inhibitors / administration & dosage
  • Breast Neoplasms / complications
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / pathology
  • Cell Proliferation / drug effects
  • Cyclooxygenase 2 / biosynthesis
  • Cyclooxygenase 2 Inhibitors / administration & dosage
  • Dinoprostone / biosynthesis*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Interleukin-6 / antagonists & inhibitors
  • Interleukin-6 / genetics*
  • Interleukin-6 / immunology
  • MCF-7 Cells
  • Obesity / complications
  • Obesity / genetics*
  • Obesity / pathology


  • Aromatase Inhibitors
  • Cyclooxygenase 2 Inhibitors
  • Interleukin-6
  • Aromatase
  • Cyclooxygenase 2
  • Dinoprostone