Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast.
Prolyl-isomerase Pin1 controls normal and cancer stem cells of the breast.
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DOI：
10.1002/emmm.201302909
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发表时间：
2014-01
影响因子：
11.1
通讯作者：
Del Sal, Giannino
中科院分区：
文献类型：
--
作者：
Rustighi, Alessandra;Zannini, Alessandro;Tiberi, Luca;Sommaggio, Roberta;Piazza, Silvano;Sorrentino, Giovanni;Nuzzo, Simona;Tuscano, Antonella;Eterno, Vincenzo;Benvenuti, Federica;Santarpia, Libero;Aifantis, Iannis;Rosato, Antonio;Bicciato, Silvio;Zambelli, Alberto;Del Sal, Giannino
乳腺上皮干细胞是维持组织完整性的基础。癌症干细胞（CSCs）与治疗耐药和疾病复发有关，其恶性特性的分子基础仍然知之甚少。我们发现乳腺的正常干细胞和CSCs都受脯氨酸异构酶Pin1的控制。从机制上讲，在与Pin1、Notch1和Notch4相互作用后，细胞命运的关键调节因子通过其主要的泛素连接酶Fbxw7α逃避蛋白酶体降解。在功能上，我们发现Fbxw7α通过抑制Notch活性作为乳腺CSCs扩张的重要负调节因子，但Notch/Pin1有源电路的建立反对这种作用，从而促进乳腺CSCs的自我更新、肿瘤生长和体内转移。在人类乳腺癌中，尽管Fbxw7α表达，高水平的Pin1维持Notch信号，这与不良预后相关。抑制Pin1有望通过CSC耗竭以及恢复药物敏感性来恢复侵袭性表型，这对乳腺癌的治疗具有相关意义。
Mammary epithelial stem cells are fundamental to maintain tissue integrity. Cancer stem cells (CSCs) are implicated in both treatment resistance and disease relapse, and the molecular bases of their malignant properties are still poorly understood. Here we show that both normal stem cells and CSCs of the breast are controlled by the prolyl-isomerase Pin1. Mechanistically, following interaction with Pin1, Notch1 and Notch4, key regulators of cell fate, escape from proteasomal degradation by their major ubiquitin-ligase Fbxw7α. Functionally, we show that Fbxw7α acts as an essential negative regulator of breast CSCs' expansion by restraining Notch activity, but the establishment of a Notch/Pin1 active circuitry opposes this effect, thus promoting breast CSCs self-renewal, tumor growth and metastasis in vivo. In human breast cancers, despite Fbxw7α expression, high levels of Pin1 sustain Notch signaling, which correlates with poor prognosis. Suppression of Pin1 holds promise in reverting aggressive phenotypes, through CSC exhaustion as well as recovered drug sensitivity carrying relevant implications for therapy of breast cancers.
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DOI：
10.1186/bcr920
发表时间：
2004
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Dontu G;Jackson KW;McNicholas E;Kawamura MJ;Abdallah WM;Wicha MS
通讯作者：
Wicha MS
影响因子：
10.5
作者：
Dontu, G;Abdallah, WM;Wicha, MS
通讯作者：
Wicha, MS
影响因子：
64.8
作者：
Guarani V;Deflorian G;Franco CA;Krüger M;Phng LK;Bentley K;Toussaint L;Dequiedt F;Mostoslavsky R;Schmidt MHH;Zimmermann B;Brandes RP;Mione M;Westphal CH;Braun T;Zeiher AM;Gerhardt H;Dimmeler S;Potente M
通讯作者：
Potente M
影响因子：
11.2
作者：
Ding Q;Huo L;Yang JY;Xia W;Wei Y;Liao Y;Chang CJ;Yang Y;Lai CC;Lee DF;Yen CJ;Chen YJ;Hsu JM;Kuo HP;Lin CY;Tsai FJ;Li LY;Tsai CH;Hung MC
通讯作者：
Hung MC
影响因子：
50.3
作者：
Domingo-Domenech J;Vidal SJ;Rodriguez-Bravo V;Castillo-Martin M;Quinn SA;Rodriguez-Barrueco R;Bonal DM;Charytonowicz E;Gladoun N;de la Iglesia-Vicente J;Petrylak DP;Benson MC;Silva JM;Cordon-Cardo C
通讯作者：
Cordon-Cardo C