PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.
PIM1 kinase regulates cell death, tumor growth and chemotherapy response in triple-negative breast cancer.
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DOI：
10.1038/nm.4198
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发表时间：
2016-11
期刊：
影响因子：
82.9
通讯作者：
Tutt AN
中科院分区：
文献类型：
--
作者：
Brasó-Maristany F;Filosto S;Catchpole S;Marlow R;Quist J;Francesch-Domenech E;Plumb DA;Zakka L;Gazinska P;Liccardi G;Meier P;Gris-Oliver A;Cheang MC;Perdrix-Rosell A;Shafat M;Noël E;Patel N;McEachern K;Scaltriti M;Castel P;Noor F;Buus R;Mathew S;Watkins J;Serra V;Marra P;Grigoriadis A;Tutt AN
三阴性乳腺癌（TNBC）预后不良，缺乏靶向治疗。基因组数据集的询问鉴定了TNBC中增加的PIM 1拷贝数驱动的表达。在乳腺癌和非恶性乳腺上皮细胞模型中的RNA干扰揭示了TNBC细胞中PIM 1对增殖和凋亡保护的依赖性，而在非恶性细胞中不存在。PIM 1敲低降低了BCL 2表达，动态BH 3谱分析显示，PIM 1阻止了TNBC细胞系中细胞介导的凋亡。PIM 1表达与几种MYC转录特征相关，并通过调节c-MYC和MYC靶点（包括MCL 1）的转录促进细胞群生长。泛PIM激酶抑制剂AZD 1208抑制生长并使TNBC细胞系、异种移植物和患者来源的异种移植物对标准护理化疗敏感。我们将PIM 1鉴定为TNBC中的恶性细胞选择性靶点，说明了与MYC活化、抗凋亡BCL 2和MCL 1的调节、已建立的TNBC致癌蛋白SHP 2和EPHA 2以及细胞周期抑制剂p27的关系。最后，我们确定了PIM 1抑制剂的潜在用途，以消除TNBC对TNBC标准护理化疗诱导的凋亡性细胞死亡的高阈值。
Triple-negative breast cancers (TNBCs) have poor prognosis and lack targeted therapies. Interrogation of genomic datasets identified increased PIM1 copy number-driven expression in TNBC. RNA interference in breast cancer and non-malignant mammary epithelial cell models revealed a PIM1 dependency in TNBC cells for proliferation and apoptotic protection, absent in non-malignant cells. PIM1 knockdown reduced BCL2 expression, and dynamic BH3 profiling analysis revealed that PIM1 prevents mitochondrial-mediated apoptosis in TNBC cell lines. PIM1 expression associates with several MYC-transcriptional signatures and promotes cell population growth through regulation of c-MYC and transcription of MYC-targets, including MCL1. The pan-PIM kinase inhibitor AZD1208 inhibited growth and sensitized TNBC cell lines, xenografts and patient-derived xenografts to standard of care chemotherapy. We identify PIM1 as a malignant cell-selective target in TNBC, illustrating relationships with MYC activation, regulation of anti-apoptotic BCL2 and MCL1, established TNBC oncogenic proteins SHP2 and EPHA2 and cell cycle inhibitor p27. Finally we identify a potential use of PIM1 inhibitors to abrogate TNBC's high threshold to TNBC standard of care chemotherapy induced apoptotic cell death.
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DOI：
10.1158/1078-0432.ccr-13-0799
发表时间：
2013-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Masuda H;Baggerly KA;Wang Y;Zhang Y;Gonzalez-Angulo AM;Meric-Bernstam F;Valero V;Lehmann BD;Pietenpol JA;Hortobagyi GN;Symmans WF;Ueno NT
通讯作者：
Ueno NT
影响因子：
64.8
作者：
Curtis, Christina;Shah, Sohrab P.;Chin, Suet-Feung;Turashvili, Gulisa;Rueda, Oscar M.;Dunning, Mark J.;Speed, Doug;Lynch, Andy G.;Samarajiwa, Shamith;Yuan, Yinyin;Graef, Stefan;Ha, Gavin;Haffari, Gholamreza;Bashashati, Ali;Russell, Roslin;McKinney, Steven;Langerod, Anita;Green, Andrew;Provenzano, Elena;Wishart, Gordon;Pinder, Sarah;Watson, Peter;Markowetz, Florian;Murphy, Leigh;Ellis, Ian;Purushotham, Arnie;Borresen-Dale, Anne-Lise;Brenton, James D.;Tavare, Simon;Caldas, Carlos;Aparicio, Samuel
通讯作者：
Aparicio, Samuel
影响因子：
4.3
作者：
Labisso, Wajana L.;Wirth, Matthias;Schneider, Guenter
通讯作者：
Schneider, Guenter
影响因子：
28.2
作者：
Balko JM;Giltnane JM;Wang K;Schwarz LJ;Young CD;Cook RS;Owens P;Sanders ME;Kuba MG;Sánchez V;Kurupi R;Moore PD;Pinto JA;Doimi FD;Gómez H;Horiuchi D;Goga A;Lehmann BD;Bauer JA;Pietenpol JA;Ross JS;Palmer GA;Yelensky R;Cronin M;Miller VA;Stephens PJ;Arteaga CL
通讯作者：
Arteaga CL
影响因子：
11.5
作者：
Andre, Fabrice;Job, Bastien;Pusztai, Lajos
通讯作者：
Pusztai, Lajos