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

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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/m2) or normal weight (N; BMI 18.5–24.9 kg/m2) 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.

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Acknowledgments

LB was supported by a Predoctoral Traineeship Award from the United States Department of Defense, Breast Cancer Research Program (BCRP) of the Congressionally Directed Medical Research Programs (CDMRP) (Award Number W81XWH-11-1-0132).

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Standards

The experiments described here comply with the current laws of the country in which they were performed.

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Authors and Affiliations

  1. Department of Nutrition, University of North Carolina at Chapel Hill, 135 Dauer Drive, McGavran-Greenberg Hall, Chapel Hill, NC, 27599, USA

    Laura W. Bowers & Stephen D. Hursting

  2. Division of Hematology and Medical Oncology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Andrew J. Brenner

  3. Department of Obstetrics and Gynecology, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX, 78229, USA

    Rajeshwar R. Tekmal

  4. Department of Nutritional Sciences, University of Texas at Austin, 1400 Barbara Jordan Blvd, R1800, Austin, TX, 78723-3092, USA

    Linda A. deGraffenried

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  1. Laura W. Bowers
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Correspondence to Laura W. Bowers.

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Bowers, L.W., Brenner, A.J., Hursting, S.D. et al. Obesity-associated systemic interleukin-6 promotes pre-adipocyte aromatase expression via increased breast cancer cell prostaglandin E2 production. Breast Cancer Res Treat 149, 49–57 (2015). https://doi.org/10.1007/s10549-014-3223-0

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  • DOI: https://doi.org/10.1007/s10549-014-3223-0

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