TUMOR SUPPRESSOR AND GROWTH FACTORS IN TUMORIGENESIS

提出了一种基因打靶小鼠的遗传学研究方案 缺乏乳腺癌易感基因功能的突变体 Brca 1和Brca 2，并检查它们是否可以作为模型模拟 人类对乳腺肿瘤的易感性。绕过胚胎的致命性 与Brca 1和Brca 2功能的整体消融相关， 这些基因只在乳腺中被条件性的 使用cre/loxP系统的靶向诱变。使用这些模型， 育种计划，乳腺肿瘤进展将在一个 受胰岛素样生长影响的生长信号传导的背景无效 IGFs（胰岛素样生长因子）最近的证据表明， IGF系统在细胞转化和肿瘤发生中提供了强有力的 建议的遗传分析的指示。 为了启动我们的调查，我们提出了一个假设 假设肿瘤的发展将被阻止或减少， 主要信号传导途径遗传背景无效的严重程度 调节生长。因此，在小鼠中乳腺肿瘤的发展缺乏 BRCA 1或BRCA 2肿瘤抑制剂将在不存在 1型IGF受体（IGF 1 R）。同样，各种肿瘤的进展 将通过结合p53和Igf 1 r无效突变进行研究，因为 p53抑癌基因通路与胰岛素样生长因子的关系 已经被注意到了。 拟议的研究，其优点是，问题将是 在整个实验生物体的背景下进行体内处理， 应允许在定义的 突变及其表型后果的多步骤过程， 致癌作用，并可能提供实用的信息， 对最终确定候选目标的重要性 合理的治疗方案。

A genetic research program is proposed to generate by gene targeting mouse mutants lacking the functions of the breast cancer susceptibility genes Brca1 and Brca2 and examine whether they could serve as model simulating human predisposition to mammary tumors. To bypass the embryonic lethality associated with the global ablation of the Brca1 and Brca2 functions, these genes will be inactivated only in the mammary glands by conditional targeted mutagenesis using the cre/loxP system. Using these models in a breeding program, mammary tumor progression will be investigated in a background null for growth signaling effected by insulin-like growth factors (IGFs). Recent evidence demonstrating a central involvement of the IGF system in cell transformation and tumorigenesis has provided a strong indication for the proposed genetic analyses. To initiate our investigation, we have advanced a working hypothesis postulating that tumor development will be prevented or reduced in severity in a genetic background null for a major signalling pathway regulating growth. Thus, the development of mammary tumors in mice lacking the BRCA1 or BRCA2 tumor suppressors will be examine in the absence of the type 1 IGF receptor (IGF1R). Similarly, progression of a variety of tumors will be studied by combining p53 and Igf1r null mutations, because relationships between the pathway of the p53 tumor suppressor and the IGFs have been noted. The proposed studies, which have the advantage that questions will be addressed in vivo in the context of the entire experimental organism, should allow the establishment of causal relationships between defined mutations and their phenotypic consequences for the multi-step process of carcinogenesis, and are likely to provide information of practical significance for the eventual identification of candidate targets for rational therapeutic regimes.