脂肪组织
线粒体
细胞生物学
细胞生长
生物
PI3K/AKT/mTOR通路
氧化磷酸化
乳腺癌
癌症研究
内分泌学
内科学
癌症
信号转导
生物化学
医学
遗传学
作者
Liu Shuchen,Alberto Benito-Martín,Fanny A. Pelissier Vatter,Sarah Z Hanif,Catherine Liu,Priya Bhardwaj,Praveen Sethupathy,Alaa R. Farghli,Phoebe Piloco,Paul K. Paik,Malik Mushannen,Xue Dong,David M. Otterburn,Leslie E. Cohen,Rohan Bareja,Jan Krumsiek,Leona Cohen‐Gould,Samuel Calto,Jason A. Spector,Olivier Elemento,David Lyden,Kristy A. Brown
标识
DOI:10.15252/embr.202357339
摘要
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.
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