Impact of diabetes on promoting the growth of breast cancer

查看全文 作　　者：Ping-Chieh [1]Chou;Hyun Ho [2,3]Choi;Yizhi [2,3]Huang;Enrique Fuentes-[1]Mattei;Guermarie Velazquez-[1]Torres;Fanmao [1]Zhang;Liem [1]Phan;Jaehyuk [4]Lee;Yanxia [5]Shi;James [4]A.Bankson;Yun [6]Wu;Huamin [6]Wang;Ruiying [1]Zhao;Sai-Ching Jim [7]Yeung;Mong-Hong [1,2,3]Lee

机构地区：[1]Department of Molecular and Cellular Oncology,the University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA;[2]Guangdong Provincial Key laboratory of Colorectal and Pelvic Floor Disease,the Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong 510020,P.R.China;[3]Research Institute of Gastroenterology the Sixth Affiliated Hospital of Sun Yat-sen University,Guangzhou,Guangdong 510020,P.R.China;[4]Department of Imaging Physics,the University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA;[5]Department of Medical Oncology,Sun Yat-sen University Cancer Center,Guangzhou,Guangdong 510060,P.R.China;[6]Department of Pathology,the University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA;[7]Department of Emergency Medicine,the University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA

出　　处：《Cancer Communications》索引2021年第41卷第5期,共18页

基　　金：Fidelity Foundation,Grant/Award Number:2020YFA0803300;Shenzhen Municipal Government;NationalNatural Science Foundation of China,Grant/Award Numbers:81702749,81630072,81773098,81803568,8160242. 摘　　要：Background:Type Ⅱ diabetes mellitus(DM2)is a significant risk factor for cancers,including breast cancer.However,a proper diabetic breast cancer mouse model is notwell-established for treatment strategy design.Additionally,the precise diabetic signaling pathways that regulate cancer growth remain unresolved.In the present study,we established a suitable mouse model and demonstrated the pathogenic role of diabetes on breast cancer progression.Methods:We successfully generated a transgenic mouse model of human epidermal growth factor receptor 2 positive(Her2^(+) or ERBB2)breast cancer with DM2 by crossing leptin receptor mutant(Lepr^(db/+))mice with (MMTV-ErbB2/neu)mice.Themousemodelswere administrated with antidiabetic drugs to assess the impacts of controlling DM2 in affecting tumor growth.Magnetic resonance spectroscopic imaging was employed to analyze the tumor metabolism.Results:Treatment with metformin/rosiglitazone in MMTV-ErbB2/Lepr^(db/db) mousemodel reduced serum insulin levels,prolonged overall survival,decreased cumulative tumor incidence,and inhibited tumor progression.Anti-insulin resistance medications also inhibited glycolytic metabolism in tumors in vivo as indicated by the reduced metabolic flux of hyperpolarized ^(13)C pyruvate-to-lactate reaction.The tumor cells from MMTV-ErbB2/Lepr^(db/db) transgenic mice treated with metformin had reprogrammed metabolism by reducing levels of both oxygen consumption and lactate production.Metformin decreased the expression of Myc and pyruvate kinase isozyme 2(PKM2),leading to metabolism reprogramming.Moreover,metformin attenuated the mTOR/AKT signaling pathway and altered adipokine profiles.Conclusions:MMTV-ErbB2/Lepr^(db/db) mouse model was able to recapitulate diabetic HER2^(+) human breast cancer.Additionally,our results defined the signaling pathways deregulated in HER2^(+) breast cancer under diabetic condition,which can be intervened by anti-insulin resistance therapy. 关键词：DIABETES human epidermal growth factor receptor 2 breast cancer METFORMIN METABOLISM

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Impact of diabetes on promoting the growth of breast cancer

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