Breast adipose tissue‐derived extracellular vesicles from obese women alter tumor cell metabolism

Abstract

Breast adipose tissue is an important contributor to the obesity–breast cancer link. Extracellular vesicles (EVs) are nanosized particles containing selective cargo, such as miRNAs, that act locally or circulate to distant sites to modulate target cell functions. Here, we find that long‐term education of breast cancer cells with EVs obtained from breast adipose tissue of women who are overweight or obese (O‐EVs) results in increased proliferation. RNA‐seq analysis of O‐EV‐educated cells demonstrates increased expression of genes involved in oxidative phosphorylation, such as ATP synthase and NADH: ubiquinone oxidoreductase. O‐EVs increase respiratory complex protein expression, mitochondrial density, and mitochondrial respiration in tumor cells. The mitochondrial complex I inhibitor metformin reverses O‐EV‐induced cell proliferation. Several miRNAs—miR‐155‐5p, miR‐10a‐3p, and miR‐30a‐3p—which promote mitochondrial respiration and proliferation, are enriched in O‐EVs relative to EVs from lean women. O‐EV‐induced proliferation and mitochondrial activity are associated with stimulation of the Akt/mTOR/P70S6K pathway, and are reversed upon silencing of P70S6K. This study reveals a new facet of the obesity‐breast cancer link with human breast adipose tissue‐derived EVs causing metabolic reprogramming of breast cancer cells. image Long‐term education of breast cancer cells with extracellular vesicles from breast adipose tissue of women who are overweight or with obesity (O‐EVs) promotes proliferation via Akt/mTOR/P70S6K signaling and increases mitochondrial density and respiration. Several miRNAs enriched in O‐EVs orchestrate these pro‐proliferative effects. Long‐term education with O‐EVs promote proliferation of breast cancer cells in vitro and in vivo . Enhanced mitochondrial respiration is essential for the mitogenic effect of O‐EVs. Increased mitochondrial density occurs as a result of long‐term education with O‐EVs. miRNAs enriched in O‐EVs—miR‐155‐5p, miR‐10a‐3p, and miR‐30a‐3p—mimic the effects caused by O‐EVs. Inhibition of the Akt/mTOR/P70S6K pathway can reverse enhanced proliferation and respiration induced by O‐EVs.