Cooperative of Hras or Braf wiht Pten in Thyroid Carcinogenesis

描述(申请人提供)：甲状腺癌与编码受体酪氨酸激酶RET和TRK以及NRAS、HRAS、KRAS和BRAF的基因非重叠突变的高发有关。RAS家族的突变通常与滤泡性甲状腺癌(FTC)有关，而BRAF突变是乳头状甲状腺癌(PTC)中最常见的遗传缺陷。这些蛋白的一个共同性质是它们能够通过经典的MAPK途径传递信号，这被解释为MAPK在甲状腺癌的发生和维持中发挥关键作用的证据。然而，甲状腺癌也与编码磷脂酰肌醇3-激酶(PI3K)通路信号的效应基因突变有关，但在某些甲状腺肿瘤中，PI3K-AKT的结构性激活是否与MAPK协同驱动肿瘤发生过程还没有仔细的研究。RAS癌蛋白通过两条途径传递信号，而致癌的BRAF信号优先(或唯一)通过MAPK，这为在小鼠癌症模型中探索这些相互作用提供了一个有用的范例。致癌信号的强度是一个重要的变量，我们打算在这些分析中使用接近病理生理条件的遗传操作。为此，我们建立了HRAS的条件性基因靶向激活突变的小鼠，并获得了类似的BRAF模型，在Cre介导的重组后，在其内源基因启动子的控制下，各自的癌蛋白表达，从而为肿瘤的启动提供了生理刺激。在这项建议中，我们将探讨HRAs或BRAF的激活是否与肿瘤抑制基因Pten的缺失协同促进甲状腺癌的进展。根据来自人类甲状腺癌样本的信息和我们的小鼠遗传学研究的初步数据，我们假设这些癌基因与肿瘤抑制基因Pten的丢失有关。将追求以下目标：1.确定靶向敲入HrasG12V是否与甲状腺特异性Pten缺失协同诱导甲状腺细胞生长和转化为滤泡性甲状腺癌。检查甲状腺特异性Pten的缺失是否增加了表达内源性BRAF水平的小鼠甲状腺乳头状肿瘤的毒力。这项研究的目的是为了更好地了解导致甲状腺癌发生的遗传事件，并建立甲状腺癌的相关模型，以开发这种疾病的新疗法。

DESCRIPTION (provided by applicant): Thyroid cancers are associated with a high prevalence of non-overlapping mutations of the genes encoding the receptor tyrosine kinases RET and TRK, as well as of NRAS, HRAS, KRAS and BRAF. Mutations of the RAS family are commonly associated with follicular thyroid cancer (FTC), while mutations in BRAF are the most prevalent genetic defect in papillary thyroid cancer (PTC). A common property of these proteins is their ability to signal via the classical MAPK pathway, which has been interpreted as evidence for a critical role of MAPK in initiation and maintenance of thyroid cancer. However thyroid cancers are also associated with mutations of genes encoding effectors signaling along the phosphatidylinositol 3-kinase (PI3K) pathway, yet whether constitutive activation of PI3K-AKT cooperates or not in certain thyroid tumors with MAPK to drive the tumorigenic process has not been carefully explored. Ras oncoproteins signal through both pathways, whereas oncogenic Braf signals preferentially (or exclusively) through MAPK, providing a useful paradigm in which to explore these interactions in mouse cancer models. The intensity of the oncogenic signal is an important variable, and we intend to use genetic manipulations that approximate pathophysiological conditions in these analyses. For this we have generated mice with a conditional gene- targeted activating mutation of Hras, and obtained an analogous model for Braf, which after Cre-mediated recombination result in expression of the respective oncoprotein under the control of their endogenous gene promoters, hence providing a physiological stimulus for tumor initiation. This proposal we will explore whether Hras or Braf activation cooperate with loss of the tumor suppressor Pten to promote thyroid cancer progression. We hypothesize that these oncogenes cooperate with loss of the tumor suppressor Pten based on information from human thyroid cancer samples, and preliminary data from our mouse genetic studies. The following aims will be pursued: I. Determine whether targeted knock-in of HrasG12V cooperates with thyroid-specific Pten loss to induce thyroid cell growth and transformation to follicular thyroid cancer. II. Examine whether thyroid-specific loss of Pten increases the virulence of papillary thyroid tumors in mice expressing endogenous levels of oncogenic Braf. The goals of this research are to better understand the genetic events that lead to thyroid cancer development and to establish relevant models of thyroid cancer to develop new treatments for this disease.