Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer.
Snail1-dependent p53 repression regulates expansion and activity of tumour-initiating cells in breast cancer.
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Snail1依赖性p53抑制调节乳腺癌肿瘤起始细胞的扩张和活性
DOI：
10.1038/ncb3425
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发表时间：
2016-11
影响因子：
21.3
通讯作者：
Weiss SJ
中科院分区：
文献类型：
--
作者：
Ni T;Li XY;Lu N;An T;Liu ZP;Fu R;Lv WC;Zhang YW;Xu XJ;Grant Rowe R;Lin YS;Scherer A;Feinberg T;Zheng XQ;Chen BA;Liu XS;Guo QL;Wu ZQ;Weiss SJ
锌指转录因子Snail 1在乳腺癌中表达不当，与预后不良相关。在查询人类数据库时，我们发现表达高Snail 1水平的乳腺癌患者的无复发生存率显著降低，而野生型p53则没有。使用Snail 1小鼠乳腺癌的条件性敲除模型，保持野生型p53，我们发现，Snail 1通过控制癌前腺体和已建立的肿瘤中肿瘤起始细胞的扩增和活性，在肿瘤进展中起着至关重要的作用，而它不是正常乳腺发育所必需的。癌前和肿瘤性乳腺上皮细胞的生长和存活依赖于Snail 1/HDAC 1/p53三分子复合物的形成，该复合物使活性p53脱乙酰化，从而促进其蛋白酶体降解。我们的研究结果确定Snail 1作为一种分子旁路，抑制乳腺癌中野生型p53发挥的抗增殖和促凋亡作用。
The zinc-finger transcription factor Snail1 is inappropriately expressed in breast cancer and associated with poor prognosis. While interrogating human databases, we uncovered marked decreases in relapse-free survival of breast cancer patients expressing high Snail1 levels in tandem with wild-type, but not mutant, p53. Using a Snail1 conditional knockout model of mouse breast cancer that maintains wild-type p53, we find that Snail1 plays an essential role in tumour progression by controlling the expansion and activity of tumour-initiating cells in preneoplastic glands and established tumours, whereas it is not required for normal mammary development. Growth and survival of preneoplastic as well as neoplastic mammary epithelial cells is dependent on the formation of a Snail1/HDAC1/p53 tri-molecular complex that deacetylates active p53, thereby promoting its proteasomal degradation. Our findings identify Snail1 as a molecular bypass that suppresses the anti-proliferative and pro-apoptotic effects exerted by wild-type p53 in breast cancer.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
影响因子：
64.5
作者：
Jiao B;Ma H;Shokhirev MN;Drung A;Yang Q;Shin J;Lu S;Byron M;Kalantry S;Mercurio AM;Lawrence JB;Hoffmann A;Bach I
通讯作者：
Bach I
影响因子：
64.5
作者：
Cheung KJ;Gabrielson E;Werb Z;Ewald AJ
通讯作者：
Ewald AJ
影响因子：
3.3
作者：
Geradts J;de Herreros AG;Su Z;Burchette J;Broadwater G;Bachelder RE
通讯作者：
Bachelder RE
影响因子：
50.3
作者：
Ansieau, Stephane;Bastid, Jeremy;Puisieux, Alain
通讯作者：
Puisieux, Alain