Notch3 inhibits cell proliferation and tumorigenesis and predicts better prognosis in breast cancer through transactivating PTEN.
Notch3 inhibits cell proliferation and tumorigenesis and predicts better prognosis in breast cancer through transactivating PTEN.
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Notch3 通过反式激活 PTEN 抑制细胞增殖和肿瘤发生并预测乳腺癌的更好预后
DOI：
10.1038/s41419-021-03735-3
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发表时间：
2021-05-18
影响因子：
9
通讯作者：
Zhang GJ
中科院分区：
文献类型：
--
作者：
Zhang YQ;Liang YK;Wu Y;Chen M;Chen WL;Li RH;Zeng YZ;Huang WH;Wu JD;Zeng D;Gao WL;Chen CF;Lin HY;Yang RQ;Zhu JW;Liu WL;Bai JW;Wei M;Wei XL;Zhang GJ
Notch受体（Notch1-4）在包括乳腺癌在内的恶性肿瘤的发生和转移中起着至关重要的作用。虽然Notch异常激活与多种肿瘤有关，但单个受体的重要性及其在不同乳腺癌亚型中的激活机制尚不清楚。本课题组前期研究表明，Notch3可能抑制乳腺癌的发生和发展。PTEN是一种有效的肿瘤抑制因子，其功能的丧失足以促进肿瘤的发生和发展。有趣的是，许多研究表明Notch1通过结合Notch转录因子CBF-1和PTEN启动子参与PTEN的调控。在本研究中，我们发现Notch3和PTEN水平与乳腺癌细胞系的管腔表型相关。此外，我们证明Notch3通过结合PTEN启动子中的csl结合元件来反激活PTEN，并且至少部分抑制PTEN下游AKT-mTOR途径。值得注意的是，Notch3敲低可下调PTEN，促进细胞增殖和肿瘤发生。相比之下，细胞内Notch3结构域的过表达上调PTEN，抑制细胞增殖和肿瘤发生。此外，PTEN的抑制或过表达部分逆转了Notch3改变诱导的细胞增殖促进或抑制。总的来说，Notch3的表达与PTEN、ER的表达升高、Ki-67指数的降低以及累及淋巴结的发生率呈正相关，预示着乳腺癌患者更好的无复发生存期。因此，我们的研究结果表明，Notch3通过反激活PTEN表达来抑制乳腺癌的增殖和肿瘤的发生。
Notch receptors (Notch1–4) play critical roles in tumorigenesis and metastasis of malignant tumors, including breast cancer. Although abnormal Notch activation is related to various tumors, the importance of single receptors and their mechanism of activation in distinct breast cancer subtypes are still unclear. Previous studies by our group demonstrated that Notch3 may inhibit the emergence and progression of breast cancer. PTEN is a potent tumor suppressor, and its loss of function is sufficient to promote the occurrence and progression of tumors. Intriguingly, numerous studies have revealed that Notch1 is involved in the regulation of PTEN through its binding to CBF-1, a Notch transcription factor, and the PTEN promoter. In this study, we found that Notch3 and PTEN levels correlated with the luminal phenotype in breast cancer cell lines. Furthermore, we demonstrated that Notch3 transactivated PTEN by binding CSL-binding elements in the PTEN promoter and, at least in part, inhibiting the PTEN downstream AKT-mTOR pathway. Notably, Notch3 knockdown downregulated PTEN and promoted cell proliferation and tumorigenesis. In contrast, overexpression of the Notch3 intracellular domain upregulated PTEN and inhibited cell proliferation and tumorigenesis in vitro and in vivo. Moreover, inhibition or overexpression of PTEN partially reversed the promotion or inhibition of cell proliferation induced by Notch3 alterations. In general, Notch3 expression positively correlated with elevated expression of PTEN, ER, lower Ki-67 index, and incidence of involved node status and predicted better recurrence-free survival in breast cancer patients. Therefore, our findings demonstrate that Notch3 inhibits breast cancer proliferation and suppresses tumorigenesis by transactivating PTEN expression.
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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：
23.9
作者：
Bouras, Toula;Pal, Bhupinder;Visvader, Jane E.
通讯作者：
Visvader, Jane E.
影响因子：
3.8
作者：
Cohen, Brenda;Shimizu, Mamiko;Reedijk, Michael
通讯作者：
Reedijk, Michael
影响因子：
--
作者：
Hammond, M. Elizabeth H.;Hayes, Daniel F.;Temin, Sarah
通讯作者：
Temin, Sarah
影响因子：
9.7
作者：
Liang, Yuan-Ke;Zeng, De;Zhang, Guo-Jun
通讯作者：
Zhang, Guo-Jun