Igf1r as a therapeutic target in a mouse model of basal-like breast cancer
Igf1r as a therapeutic target in a mouse model of basal-like breast cancer
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DOI：
10.1073/pnas.0810221106
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发表时间：
2009-02-17
影响因子：
11.1
通讯作者：
Efstratiadis, Argiris
中科院分区：
文献类型：
--
作者：
Klinakis, Apostolos;Szabolcs, Matthias;Efstratiadis, Argiris
考虑到胰岛素样生长因子 (IGF) 信号传导失调与各种人类癌症之间的密切相关性，我们使用遗传分析和药物治疗的便捷组合来评估 1 型 IGF 受体 (Igf1r) 在乳腺肿瘤发生小鼠模型中进行靶向抗癌治疗的潜力。在这种特殊的转基因动物品系中，由于乳腺特异性过度表达组成性活性致癌Kras*（突变体Kras(G12D)），表现出Igf1r基因上调的组织病理学异质性浸润性癌极其迅速地发展。免疫表型数据和表达谱分析表明，除了少量的管腔成分外，这些小鼠肿瘤类似于基底样人类乳腺癌。这是一组预后不良的侵袭性肿瘤，目前尚无可用的靶向治疗，其中包括与 KRAS 基因座扩增相关的亚型。小鼠乳腺上皮中 Igf1r 的条件性消融非常显着地增加了 Kras* 诱导的肿瘤的潜伏期（与完整模型相比大约增加了 11 倍），而通过给予鬼臼苦素（PPP）（一种特定的 Igf1r 抑制剂）治疗荷瘤动物，导致主要形式的基底样癌的肿瘤质量急剧减少。 PPP 对人类基底样癌细胞系 MDA-MB-231 的异种移植也有效，该细胞系携带 KRAS(G13D) 突变。
Considering the strong association between dysregulated insulin-like growth factor (IGF) signaling and various human cancers, we have used an expedient combination of genetic analysis and pharmacological treatment to evaluate the potential of the type 1 IGF receptor (Igf1r) for targeted anticancer therapy in a mouse model of mammary tumorigenesis. In this particular strain of genetically modified animals, histopathologically heterogeneous invasive carcinomas exhibiting up-regulation of the Igf1r gene developed extremely rapidly by mammary gland-specific overexpression of constitutively active oncogenic Kras* (mutant Kras(G12D)). Immunophenotyping data and expression profiling analyses showed that, except for a minor luminal component, these mouse tumors resembled basal-like human breast cancers. This is a group of aggressive tumors of poor prognosis for which there is no targeted therapy currently available, and it includes a subtype correlating with KRAS locus amplification. Conditional ablation of Igf1r in the mouse mammary epithelium increased the latency of Kras*-induced tumors very significantly (approximate to 11-fold in comparison with the intact model), whereas treatment of tumor-bearing animals by administration of picropodophyllin (PPP), a specific Igf1r inhibitor, resulted in a dramatic decrease in tumor mass of the main forms of basal-like carcinomas. PPP also was effective against xenografts of the human basal-like cancer cell line MDA-MB-231, which carries a KRAS(G13D) mutation.