Identification of an integrated SV40 T/t-antigen cancer signature in aggressive human breast, prostate, and lung carcinomas with poor prognosis
Identification of an integrated SV40 T/t-antigen cancer signature in aggressive human breast, prostate, and lung carcinomas with poor prognosis
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DOI：
10.1158/0008-5472.can-07-1515
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发表时间：
2007-09-01
期刊：
影响因子：
11.2
通讯作者：
Green, Jeffrey E.
中科院分区：
文献类型：
--
作者：
Deeb, Kristin K.;Michalowska, Aleksandra M.;Green, Jeffrey E.
了解区分人类癌症子集的癌症途径的遗传结构对于开发基于其分子表达谱更好地靶向肿瘤的新疗法至关重要。在这项研究中，我们确定了一个整合的基因签名，从多个转基因模型的上皮癌固有的功能，猿猴病毒40 T/t抗原，与生物学行为和预后的几个人类上皮肿瘤。这种基因签名主要由调节细胞复制、增殖、DNA修复和凋亡的基因组成，不是一般的癌症签名。相反，它主要在具有异常p53、Rb或BRCA 1表达的肿瘤中被独特地激活，但在通过myc、ras、her 2/neu或多瘤中T癌基因的过表达而引发的肿瘤中不被激活。重要的是，表达这组基因的人乳腺、肺和前列腺肿瘤代表了具有最具侵袭性表型和预后不良的肿瘤亚群。T/t抗原标记高度预测人乳腺癌预后。由于这类上皮肿瘤通常对目前现有的标准疗法是难治的，因此这种基因签名鉴定了针对这些致命形式的癌症的新型疗法的潜在靶点。由于这些遗传靶点是使用乳腺癌、前列腺癌和肺癌T/t抗原小鼠癌症模型发现的，因此这些模型是用于集中于这些生物学重要靶点的疗法的临床前测试的基本候选模型。
Understanding the genetic architecture of cancer pathways that distinguishes subsets of human cancer is critical to developing new therapies that better target tumors based on their molecular expression profiles. In this study, we identify an integrated gene signature from multiple transgenic models of epithelial cancers intrinsic to the functions of the Simian virus 40 T/t-antigens that is associated with the biological behavior and Prognosis for several human epithelial tumors. This genetic signature, composed primarily of genes regulating cell replication, proliferation, DNA repair, and apoptosis, is not a general cancer signature. Rather, it is uniquely activated primarily in tumors with aberrant p53, Rb, or BRCA1 expression but not in tumors initiated through the overexpression of myc, ras, her2/neu, or polyoma middle T oncogenes. Importantly, human breast, lung, and prostate tumors expressing this set of genes represent subsets of tumors with the most aggressive phenotype and with poor prognosis. The T/t-antigen signature is highly predictive of human breast cancer prognosis. Because this class of epithelial tumors is generally intractable to currentiv existing standard therapies, this genetic signature identifies potential targets for novel therapies directed against these lethal forms of cancer. Because these genetic targets have been discovered using mammary, prostate, and lung T/t-antigen mouse cancer models, these models are rationale candidates for use in preclinical testing of therapies focused on these biologically important targets.