TUMOR SUPPRESSOR AND GROWTH FACTORS IN TUMORIGENESIS

提出了一种利用基因打靶小鼠产生的遗传研究程序 缺乏乳腺癌易感基因功能的突变体 BRCA1和BRCA2，并检验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BRCA1和BRCA2功能的整体消融相关联， 这些基因将只在乳腺中被有条件地灭活 使用cre/loxP系统的靶向突变。将这些模型用于 育种计划，乳腺肿瘤进展将在一项 胰岛素样生长影响的生长信号的背景为零 系数(IGF)。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大的 建议的遗传分析的适应症。 为了启动我们的调查，我们提出了一个可行的假设 假设肿瘤的发展将被预防或减少 主要信号通路的遗传背景为零的严重性 调控增长。因此，缺乏对小鼠乳腺肿瘤发生发展的研究 将在没有BRCA1或BRCA2的情况下进行肿瘤抑制基因的检查 I型IGF受体(IGF1R)。同样，各种肿瘤的进展 将通过结合p53和Igf1R零突变进行研究，因为 抑癌基因P53通路与IGFS的关系 已经被注意到了。 拟议的研究，其优势是问题将是 在整个实验有机体的背景下进行体内处理， 应允许在已定义的 突变及其在多步过程中的表型后果 癌症的发生，并可能提供实用的信息 最终确定候选目标的意义 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.