RARRES2 regulates lipid metabolic reprogramming to mediate the development of brain metastasis in triple negative breast cancer

作     者：Yi-Qun Li Fang-Zhou Sun Chun-Xiao Li Hong-Nan Mo Yan-Tong Zhou Dan Lv Jing-Tong Zhai Hai-Li Qian Fei Ma Yi-Qun Li;Fang-Zhou Sun;Chun-Xiao Li;Hong-Nan Mo;Yan-Tong Zhou;Dan Lv;Jing-Tong Zhai;Hai-Li Qian;Fei Ma

作者机构：Department of Medical OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China State Key Laboratory of Molecular OncologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China 

出 版 物：《Military Medical Research》 (军事医学研究（英文版）)

年 卷 期：2024年第11卷第1期

页      面：34-49页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by the National Natural Science Foundation of China(82203185,82230058,82172875 and 82073094) the National Key Research and Development Program of China(2021YFF1201300 and 2022YFE0103600) the CAMS Innovation Fund for Medical Sciences(CIFMS)(2021-I2M-1-014,2021-I2M-1-022,and 2022-I2M-2-001) the Open Issue of State Key Laboratory of Molecular Oncology(SKL-KF-2021-16) the Independent Issue of State Key Laboratory of Molecular Oncology(SKL-2021-16) the Beijing Hope Marathon Special Fund of Chinese Cancer Foundation(LC2020B14) 

主　　题：RARRES2 Lipid metabolic reprogramming Brain metastasis(BrM) Breast cancer 

摘      要：Background Triple negative breast cancer(TNBC),the most aggressive subtype of breast cancer,is characterized by a high incidence of brain metastasis(BrM)and a poor *** the most lethal form of breast cancer,BrM remains a major clinical challenge due to its rising incidence and lack of effective treatment *** evidence suggested a potential role of lipid metabolic reprogramming in breast cancer brain metastasis(BCBrM),but the underlying mechanisms are far from being fully *** Through analysis of BCBrM transcriptome data from mice and patients,and immunohistochemical validation on patient tissues,we identified and verified the specific down-regulation of retinoic acid receptor responder 2(RARRES2),a multifunctional adipokine and chemokine,in BrM of *** investigated the effect of aberrant RARRES2 expression of BrM in both in vitro and in vivo *** signaling pathway components were evaluated using multi-omics *** were performed to elucidate the regulation of lipid metabolic reprogramming of *** We found that downregulation of RARRES2 is specifically associated with BCBrM,and that RARRES2 deficiency promoted BCBrM through lipid metabolic ***,reduced expression of RARRES2 in brain metastatic potential TNBC cells resulted in increased levels of glycerophospholipid and decreased levels of triacylglycerols by regulating phosphatase and tensin homologue(PTEN)-mammalian target of rapamycin(mTOR)-sterol regulatory element-binding protein 1(SREBP1)signaling pathway to facilitate the survival of breast cancer cells in the unique brain *** Our work uncovers an essential role of RARRES2 in linking lipid metabolic reprogramming and the development of ***2-dependent metabolic functions may serve as potential biomarkers or therapeutic targets for BCBrM.