Modelling BRaf-dependent thyroid cancer in the mouse

描述（由申请人提供）：甲状腺癌是内分泌腺最常见的恶性肿瘤，预计2008年将有超过37，000例新发病例。虽然大多数诊断为甲状腺癌的患者不会死于这种疾病，但相当大比例的患者会发展成复发性或转移性疾病，并且编码丝氨酸/苏氨酸激酶BRaf的基因中的突变与这些特征相关。此外，BRaf突变也在低分化和未分化的甲状腺癌中检测到，这预示着预后非常差。已经为许多人类癌症类型构建了小鼠癌症模型，并且可以作为重要的实验和临床前平台。人类甲状腺癌的遗传基础已经开始被阐明，并且已经使用在人类肿瘤中鉴定的癌基因开发了甲状腺癌的小鼠模型。然而，这些模型依赖于使用异源甲状腺特异性启动子的癌基因的转基因表达，并且不能概括人类甲状腺癌的许多特征。在这项提案支持的工作中，我们将产生一系列精心构建的BRaf依赖性甲状腺癌小鼠模型，这些模型将利用内源性条件癌基因和肿瘤抑制等位基因，这些基因可以在成年小鼠中局部诱导。作为这项提议的一部分，我们还将产生一个甲状腺特异性CreER小鼠，这将对甲状腺研究界有用。我们相信，这些研究将促进我们对小鼠和人类甲状腺癌进展的细胞和分子基础的理解，进一步了解肿瘤发生过程中BRaf的下游效应子，确定新的治疗靶点，并开发用于测试新治疗药物的重要临床前模型。

DESCRIPTION (provided by applicant): Thyroid cancer is the most common malignancy of endocrine glands, and over 37,000 new cases are predicted for 2008. Although most patients diagnosed with thyroid cancer will not die from this disease, a significant proportion of patients will develop recurrent or metastatic disease, and mutations in the gene encoding the serine/threonine l<inase BRaf are associated with these features. In addition, BRaf mutations are also detected in poorly- and un-differentiated thyroid cancers that portend a very poor prognosis. Mouse models of cancer have been constructed for many human cancer types, and can serve as important experimental and pre-clinical platforms. The genetic underpinnings of human thyroid cancer have begun to be elucidated, and mouse models of thyroid cancer have been developed using oncogenes identified in human tumors. However, these models rely upon transgenic expression of the oncogene using a heterologous thyroid-specific promoter, and do not recapitulate many features of human thyroid cancer. In the work supported by this proposal we will generate a series of carefully-constructed BRaf-dependent mouse models of thyroid cancer that will utilize endogenous conditional oncogene and tumor suppressor alleles that can be focally-induced in adult mice. As part of this proposal we will also generate a thyroid-specific CreER mouse that will be useful to the thyroid research community. We believe that these studies will forward our understanding of the cellular and molecular basis of thyroid cancer progression in mouse and man, further knowledge of the downstream effectors of BRaf during tumorigenesis, identify novel therapeutic targets, and develop important pre-clinical models for testing of novel therapeutic agents.