Targeting the Akt/mTOR pathway in Brca1-deficient cancers.
Targeting the Akt/mTOR pathway in Brca1-deficient cancers.
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DOI：
10.1038/onc.2010.603
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发表时间：
2011-05-26
期刊：
影响因子：
8
通讯作者：
Yang, Q.
中科院分区：
文献类型：
--
作者：
Xiang, T.;Jia, Y.;Sherris, D.;Li, S.;Wang, H.;Lu, D.;Yang, Q.
乳腺癌易感基因1(BRCA1)在遗传性和散发性乳腺肿瘤的发生中起关键作用。然而，BRCA1缺乏导致癌症发生的原因尚不清楚。Akt激酶的激活是与人类恶性肿瘤相关的最常见的分子改变之一。据报道，Akt激酶活性增加在大多数乳腺癌中都存在。我们先前发现BRCA1表达下调或BRCA1基因突变激活Akt致癌途径。为了进一步研究BRCA1/Akt在肿瘤发生中的作用，我们分析了BRCA1/Akt在人乳腺癌标本中的表达，发现BRCA1的表达降低与Akt的磷酸化增加高度相关。与临床数据一致的是，短发夹状RNA敲除Akt1抑制了BRCA1突变细胞的细胞增殖。重要的是，Akt1的缺失显著减少了BRCA1缺乏引起的小鼠肿瘤形成。第三代哺乳动物靶向雷帕霉素(MTOR)抑制剂Palomid 529通过抑制Akt和mTOR信号通路显著抑制BRCA1缺陷的小鼠肿瘤生长。我们的结果表明Akt的激活参与了BRCA1缺陷性肿瘤的发生，mTOR通路可作为BRCA1缺陷性肿瘤治疗的新靶点。
The breast cancer susceptibility gene 1 (Brca1) has a key role in both hereditary and sporadic mammary tumorigenesis. However, the reasons why Brca1-deficiency leads to the development of cancer are not clearly understood. Activation of Akt kinase is one of the most common molecular alterations associated with human malignancy. Increased Akt kinase activity has been reported in most breast cancers. We previously found that downregulation of Brca1 expression or mutations of the Brca1 gene activate the Akt oncogenic pathway. To further investigate the role of Brca1/Akt in tumorigenesis, we analyzed Brca1/Akt expression in human breast cancer samples and found that reduced expression of Brca1 was highly correlated with increased phosphorylation of Akt. Consistent with the clinical data, knockdown of Akt1 by short-hairpin RNA inhibited cellular proliferation of Brca1 mutant cells. Importantly, depletion of Akt1 significantly reduced tumor formation induced by Brca1-deficiency in mice. The third generation inhibitor of mammalian target of rapamycin (mTOR), Palomid 529, significantly suppressed Brca1-deficient tumor growth in mice through inhibition of both Akt and mTOR signaling. Our results indicate that activation of Akt is involved in Brca1-deficiency mediated tumorigenesis and that the mTOR pathway can be used as a novel target for treatment of Brca1-deficient cancers.
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