HER2 expression identifies dynamic functional states within circulating breast cancer cells.
HER2 expression identifies dynamic functional states within circulating breast cancer cells.
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DOI：
10.1038/nature19328
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发表时间：
2016-09-01
期刊：
影响因子：
64.8
通讯作者：
Haber, Daniel A.
中科院分区：
文献类型：
--
作者：
Jordan, Nicole Vincent;Bardia, Aditya;Wittner, Ben S.;Benes, Cyril;Ligorio, Matteo;Zheng, Yu;Yu, Min;Sundaresan, Tilak K.;Licausi, Joseph A.;Desai, Rushil;O'Keefe, Ryan M.;Ebright, Richard Y.;Boukhali, Myriam;Sil, Srinjoy;Onozato, Maristela L.;Iafrate, Anthony J.;Kapur, Ravi;Sgroi, Dennis;Ting, David T.;Toner, Mehmet;Ramaswamy, Sridhar;Haas, Wilhelm;Maheswaran, Shyamala;Haber, Daniel A.
患有晚期雌激素受体阳性/HER 2阴性乳腺癌的女性中的循环肿瘤细胞（CTC）在多个疗程治疗后获得HER 2阳性亚群。与对HER 2靶向治疗高度敏感的HER 2扩增原发性乳腺癌相反，在转移性乳腺癌演变过程中获得性HER 2异质性的临床意义尚不清楚。在这里，我们分析了来自19名ER+/HER 2 −患者的CTC，其中84%的患者获得了表达HER 2的CTC。培养的CTC保持离散的HER 2+和HER 2 −亚群：HER 2 + CTC更具增殖性，但不对HER 2成瘾，这与多种信号传导途径的激活一致。HER 2 − CTC显示Notch和DNA损伤途径的激活，表现出对细胞毒性化疗的抗性，但对Notch抑制敏感。HER 2+和HER 2 − CTC自发相互转化，一种表型的细胞在四个细胞double内产生相反表型的子细胞。虽然HER 2+和HER 2 − CTC具有相当的肿瘤启动潜力，但差异增殖有利于HER 2+状态，而氧化应激或细胞毒性化疗可增强向HER 2 −表型的转化。紫杉醇和Notch抑制剂的同时治疗在原位CTC衍生的肿瘤模型中实现了肿瘤发生的持续抑制。总之，这些结果指出了患者来源的CTC内不同但相互转化的表型，有助于乳腺癌的进展和耐药性的获得。
Circulating tumor cells (CTCs) in women with advanced estrogen receptor-positive/HER2-negative breast cancer acquire a HER2-positive subpopulation following multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here, we analyzed CTCs from 19 ER+/HER2− patients, 84% of whom had acquired CTCs expressing HER2. Cultured CTCs maintain discrete HER2+ and HER2− subpopulations: HER2+ CTCs are more proliferative but not addicted to HER2, consistent with activation of multiple signaling pathways. HER2− CTCs show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2− CTCs interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. While HER2+ and HER2− CTCs have comparable tumor initiating potential, differential proliferation favors the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2− phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic CTC-derived tumor models. Together, these results point to distinct yet interconverting phenotypes within patient-derived CTCs, contributing to progression of breast cancer and acquisition of drug resistance.
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影响因子：
11.2
作者：
Ithimakin S;Day KC;Malik F;Zen Q;Dawsey SJ;Bersano-Begey TF;Quraishi AA;Ignatoski KW;Daignault S;Davis A;Hall CL;Palanisamy N;Heath AN;Tawakkol N;Luther TK;Clouthier SG;Chadwick WA;Day ML;Kleer CG;Thomas DG;Hayes DF;Korkaya H;Wicha MS
通讯作者：
Wicha MS
影响因子：
8
作者：
Osipo, C.;Patel, P.;Miele, L.
通讯作者：
Miele, L.
影响因子：
17.1
作者：
Ozkumur E;Shah AM;Ciciliano JC;Emmink BL;Miyamoto DT;Brachtel E;Yu M;Chen PI;Morgan B;Trautwein J;Kimura A;Sengupta S;Stott SL;Karabacak NM;Barber TA;Walsh JR;Smith K;Spuhler PS;Sullivan JP;Lee RJ;Ting DT;Luo X;Shaw AT;Bardia A;Sequist LV;Louis DN;Maheswaran S;Kapur R;Haber DA;Toner M
通讯作者：
Toner M
DOI：
10.1126/science.1253533
发表时间：
2014-07-11
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Yu M;Bardia A;Aceto N;Bersani F;Madden MW;Donaldson MC;Desai R;Zhu H;Comaills V;Zheng Z;Wittner BS;Stojanov P;Brachtel E;Sgroi D;Kapur R;Shioda T;Ting DT;Ramaswamy S;Getz G;Iafrate AJ;Benes C;Toner M;Maheswaran S;Haber DA
通讯作者：
Haber DA
影响因子：
8.8
作者：
Pandya, K.;Meeke, K.;Clementz, A. G.;Rogowski, A.;Roberts, J.;Miele, L.;Albain, K. S.;Osipo, C.
通讯作者：
Osipo, C.