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J Exp Med. 2019 Jun 3;216(6):1345-1358. doi: 10.1084/jem.20181616. Epub 2019 May 3.

Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer.

Author information

1
Committee on Cancer Biology, The University of Chicago, Chicago, IL.
2
Ben May Department for Cancer Research, The University of Chicago, Chicago, IL.
3
Department of Surgery and Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine of Northwestern University, Northwestern University, Chicago, IL.
4
Center for Clinical Cancer Genetics and Global Health, Department of Medicine, The University of Chicago, Chicago, IL.
5
School of Cardiovascular Medicine and Sciences, King's College, London British Hearth Foundation Centre, London, UK.
6
Committee on Cancer Biology, The University of Chicago, Chicago, IL mrosner@uchicago.edu.
7
Committee on Cancer Biology, The University of Chicago, Chicago, IL levb@uchicago.edu.
8
Committee on Molecular Metabolism and Nutrition, The University of Chicago, Chicago, IL.

Abstract

Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Here, we show that obesity reprograms mammary adipose tissue macrophages to a pro-inflammatory metabolically activated phenotype (MMe) that alters the niche to support tumor formation. Unlike pro-inflammatory M1 macrophages that antagonize tumorigenesis, MMe macrophages are pro-tumorigenic and represent the dominant macrophage phenotype in mammary adipose tissue of obese humans and mice. MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)-dependent manner, which signals through glycoprotein 130 (GP130) on TNBC cells to promote stem-like properties including tumor formation. Deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates obesity-augmented TNBC stemness. Moreover, weight loss reverses the effects of obesity on MMe macrophage inflammation and TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue as a mechanism for promoting TNBC stemness and tumorigenesis during obesity.

PMID:
31053611
PMCID:
PMC6547867
[Available on 2019-12-03]
DOI:
10.1084/jem.20181616

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