Suppression of Akt-mTOR pathway-a novel component of oncogene induced DNA damage response barrier in breast tumorigenesis.
Suppression of Akt-mTOR pathway-a novel component of oncogene induced DNA damage response barrier in breast tumorigenesis.
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DOI：
10.1371/journal.pone.0097076
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Bedrosian I
中科院分区：
文献类型：
--
作者：
Bhardwaj A;Rosen D;Liu M;Liu Y;Hao Q;Ganesan N;Etzel CJ;Gullett A;Albarracin CT;Bedrosian I
DNA损伤被认为与肿瘤进展直接相关，通过激活肿瘤抑制基因突变和扩增致癌基因，最终导致基因组不稳定。DNA损伤引起DNA损伤反应（DDR）的激活，这是基因毒性胁迫下维持基因组完整性的重要细胞机制。虽然细胞对基因毒性应激的反应已经在癌症模型中得到了广泛的研究，但对癌前环境中细胞对致癌应激的反应知之甚少。在本研究中，通过使用浸润性乳腺癌不同风险水平（正常、增生性乳腺疾病和原位导管癌）女性的乳腺组织样本，我们发现DNA损伤与浸润性乳腺癌的风险呈负相关。同样，在基于MCF10A的体外模型系统中，我们通过稳定克隆cyclin E在患者样本中重现了高DNA损伤条件，我们发现高水平的癌基因通过触发对主要增殖途径（AKT）的抑制来诱导DNA损伤，抑制细胞生长并通过自噬导致细胞死亡。这些数据表明，AKT-mTOR通路是永生化的“正常样”乳腺细胞中致癌基因诱导的DNA损伤反应的一个新组成部分，其抑制可能有助于抑制乳腺肿瘤的生长和发生。
DNA damage has been thought to be directly associated with the neoplastic progression by enabling mutations in tumor suppressor genes and activating/and amplifying oncogenes ultimately resulting in genomic instability. DNA damage causes activation of the DNA damage response (DDR) that is an important cellular mechanism for maintaining genomic integrity in the face of genotoxic stress. While the cellular response to genotoxic stress has been extensively studied in cancer models, less is known about the cellular response to oncogenic stress in the premalignant context. In the present study, by using breast tissues samples from women at different risk levels for invasive breast cancer (normal, proliferative breast disease and ductal carcinoma in situ) we found that DNA damage is inversely correlated with risk of invasive breast cancer. Similarly, in MCF10A based in vitro model system where we recapitulated high DNA damage conditions as seen in patient samples by stably cloning in cyclin E, we found that high levels of oncogene induced DNA damage, by triggering inhibition of a major proliferative pathway (AKT), inhibits cell growth and causes cells to die through autophagy. These data suggest that AKT-mTOR pathway is a novel component of oncogene induced DNA damage response in immortalized ‘normal-like’ breast cells and its suppression may contribute to growth arrest and arrest of the breast tumorigenesis.
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影响因子：
3.7
作者：
Kadota M;Yang HH;Gomez B;Sato M;Clifford RJ;Meerzaman D;Dunn BK;Wakefield LM;Lee MP
通讯作者：
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影响因子：
64.8
作者：
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64.8
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影响因子：
6.6
作者：
Bartkova, Jirina;Tommiska, Johanna;Bartek, Jiri
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