Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice
Myc is a Notch1 transcriptional target and a requisite for Notch1-induced mammary tumorigenesis in mice
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DOI：
10.1073/pnas.0603371103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
Efstratiadis, Argiris
中科院分区：
文献类型：
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作者：
Klinakis, Apostolos;Szaboics, Matthias;Efstratiadis, Argiris
为了探索异常Notch 1信号传导在乳腺癌发病机制中的潜在参与，我们使用了转基因小鼠模型。在这些动物中，小鼠乳腺肿瘤病毒LTR驱动的Notch 1受体（N1（1c））的组成性活性细胞内结构域的表达导致泌乳依赖性乳腺肿瘤的发展，这些肿瘤在腺体退化后消退，但在随后的妊娠中发展为非消退的浸润性腺癌。Myc在这些肿瘤中的上调促使了对乳腺癌发生中Notch 1/Myc潜在功能关系的遗传学研究。Mycin乳腺上皮的条件性消融防止了消退N1（1c）肿瘤的诱导，也降低了非消退癌的发生率，其发展具有显著增加的潜伏期。分子分析表明，小鼠和人Myc基因都是N1（1c）的直接转录靶点，通过其下游的Cbf 1转录效应子发挥作用。与这种机制联系一致，Notch 1和Myc表达在38%的受检人乳腺癌中通过免疫染色呈正相关。
To explore the potential involvement of aberrant Notch1 signaling in breast cancer pathogenesis, we have used a transgenic mouse model. In these animals, mouse mammary tumor virus LTR-driven expression of the constitutively active intracellular domain of the Notch1 receptor (N1(1c)) causes development of lactation-dependent mammary tumors that regress upon gland involution but progress to nonregressing, invasive adenocarcinomas in subsequent pregnancies. Up-regulation of Myc in these tumors prompted a genetic investigation of a potential Notch1/Myc functional relationship in breast carcinogenesis. Conditional ablation of Mycin the mammary epithelium prevented the induction of regressing N1(1c) neoplasms and also reduced the incidence of nonregressing carcinomas, which developed with significantly increased latency. Molecular analyses revealed that both the mouse and human Myc genes are direct transcriptional targets of N1(1c) acting through its downstream Cbf1 transcriptional effector. Consistent with this mechanistic link, Notch1 and Myc expression is positively correlated by immuno-staining in 38% of examined human breast carcinomas.