Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency.
Rb inactivation accelerates neoplastic growth and substitutes for recurrent amplification of cIAP1, cIAP2 and Yap1 in sporadic mammary carcinoma associated with p53 deficiency.
复制标题
DOI：
10.1038/onc.2010.300
复制
发表时间：
2010-10-21
期刊：
影响因子：
8
通讯作者：
Nikitin, A. Y.
中科院分区：
文献类型：
--
作者：
Cheng, L.;Zhou, Z.;Flesken-Nikitin, A.;Toshkov, I. A.;Wang, W.;Camps, J.;Ried, T.;Nikitin, A. Y.
遗传定义的小鼠模型提供了一个重要的工具来识别与人类癌症发病机制相关的关键继发性遗传改变。我们使用新生成的MMTV-Cre105Ayn小鼠严格灭活乳腺上皮中的p53和/或Rb，并确定与这些基因缺失相关的复发性基因组变化。p53失活导致雌激素受体阳性雷洛昔芬反应性乳腺癌的形成，具有腔内b亚型的特征。Rb缺乏不足以引发癌变，但会促进与p53失活相关的肿瘤的基因组不稳定性和生长速度。对乳腺癌的全基因组分析发现，染色体9A1带有一个复发性扩增，该位点与人类11q22同源，包含原癌基因cIAP1 （Birc2）、cIAP2 （Birc3）和Yap1。有趣的是，该扩增子优先在携带野生型Rb的肿瘤中检测到。然而，根据基因敲低实验，这三个基因在p53和Rb失活的肿瘤中都过表达，可能是由于e2f介导的反激活，并协同致癌。这些发现建立了腔内B亚型乳腺癌的模型，确定了cIAP1、cIAP2和Yap共表达在乳腺癌发生中的关键作用，并解释了cIAP1、cIAP2和Yap1在一些常见rb缺乏的肿瘤（如乳腺癌）中缺乏复发性扩增的原因。
Genetically defined mouse models offer an important tool to identify critical secondary genetic alterations with relevance to human cancer pathogenesis. We used newly generated MMTV-Cre105Ayn mice to inactivate p53 and/or Rb strictly in the mammary epithelium and to determine recurrent genomic changes associated with deficiencies of these genes. p53 inactivation led to formation of estrogen receptor positive raloxifene-responsive mammary carcinomas with features of luminal subtype B. Rb deficiency was insufficient to initiate carcinogenesis but promoted genomic instability and growth rate of neoplasms associated with p53 inactivation. Genome-wide analysis of mammary carcinomas identified a recurrent amplification at chromosome band 9A1, a locus orthologous to human 11q22, which contains protooncogenes cIAP1 (Birc2), cIAP2 (Birc3) and Yap1. Interestingly, this amplicon was preferentially detected in carcinomas carrying wild-type Rb. However, all three genes were overexpressed in carcinomas with p53 and Rb inactivation, likely due to E2F-mediated transactivation, and cooperated in carcinogenesis according to gene knockdown experiments. These findings establish a model of luminal subtype B mammary carcinoma, identify critical role of cIAP1, cIAP2 and Yap co-expression in mammary carcinogenesis and provide an explanation for the lack of recurrent amplifications of cIAP1, cIAP2 and Yap1 in some tumors with frequent Rb-deficiency, such as mammary carcinoma.
登录
查看更多内容
影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
4.4
作者：
Hu, Zhiyuan;Fan, Cheng;Perou, Charles M.
通讯作者：
Perou, Charles M.
影响因子：
30.8
作者：
Jonkers, J;Meuwissen, R;Berns, A
通讯作者：
Berns, A
影响因子：
11.2
作者：
Ma O;Cai WW;Zender L;Dayaram T;Shen J;Herron AJ;Lowe SW;Man TK;Lau CC;Donehower LA
通讯作者：
Donehower LA