TY - JOUR T1 - Metabolically activated macrophages in mammary adipose tissue link obesity to triple-negative breast cancer JF - bioRxiv DO - 10.1101/370627 SP - 370627 AU - Payal Tiwari AU - Ariane Blank AU - Chang Cui AU - Kelly Q. Schoenfelt AU - Guolin Zhou AU - Yanfei Xu AU - Ajay M. Shah AU - Seema A. Khan AU - Marsha Rich Rosner AU - Lev Becker Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/07/17/370627.abstract N2 - Obesity is associated with increased incidence and severity of triple-negative breast cancer (TNBC); however, mechanisms underlying this relationship are incompletely understood. Macrophages, which accumulate in adipose tissue and are activated during obesity, are an attractive mechanistic link. Here, we show that, during obesity, murine and human mammary adipose tissue macrophages adopt a pro-inflammatory, metabolically- activated (MMe) macrophage phenotype that promotes TNBC stem-like markers and functions, including increased tumorsphere growth in vitro and tumor-initiating potential in vivo. We demonstrate that MMe macrophages release cytokines in an NADPH oxidase 2 (NOX2)-dependent manner that signal through glycoprotein 130 (GP130) on TNBC cells to promote their stem-like properties. Accordingly, deleting Nox2 in myeloid cells or depleting GP130 in TNBC cells attenuates the ability of obesity to drive TNBC tumor formation. Our studies implicate MMe macrophage accumulation in mammary adipose tissue during obesity as a mechanism for promoting TNBC stemness and tumorigenesis.HIGHLIGHTS⁘ Obesity promotes TNBC tumor formation and stemness.⁘ Mammary adipose tissue macrophages are metabolically activated (MMe) in obese mice and humans.⁘ MMe macrophages in mammary adipose tissue contribute to obesity-induced stemness.⁘ MMe macrophages promote TNBC stemness through GP130 signaling. ER -