Cooperative of Hras or Braf wiht Pten in Thyroid Carcinogenesis

描述（由申请人提供）：甲状腺癌与编码受体酪氨酸激酶RET和TRK以及NRAS、HRAS、KRAS和BRAF的基因的非重叠突变的高发率相关。RAS家族突变通常与滤泡性甲状腺癌（FTC）相关，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特性是它们能够通过经典的MAPK通路发出信号，这被解释为MAPK在甲状腺癌的发生和维持中起关键作用的证据。然而，甲状腺癌也与编码磷脂酰肌醇3-激酶（PI3K）信号通路效应因子的基因突变有关，但在某些甲状腺肿瘤中，PI3K- akt的组成性激活是否与MAPK合作驱动致瘤过程尚未得到仔细探讨。Ras癌蛋白通过这两种途径发出信号，而致癌Braf优先（或专门）通过MAPK发出信号，这为探索小鼠癌症模型中的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近似病理生理条件的遗传操作。为此，我们产生了条件基因靶向激活突变Hras的小鼠，并获得了Braf的类似模型，经过cre介导的重组后，在内源性基因启动子的控制下，各自的癌蛋白表达，从而为肿瘤的发生提供了生理刺激。我们将探讨Hras或Braf激活是否与肿瘤抑制因子Pten的缺失协同促进甲状腺癌的进展。基于人类甲状腺癌样本的信息和小鼠遗传研究的初步数据，我们假设这些致癌基因与肿瘤抑制因子Pten的缺失合作。研究目的如下：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转化为滤泡性甲状腺癌。2。研究甲状腺特异性Pten缺失是否会增加表达内源性致癌Braf的小鼠甲状腺乳头状肿瘤的毒力。本研究的目的是更好地了解导致甲状腺癌发展的遗传事件，并建立甲状腺癌的相关模型，以开发新的治疗方法。

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.