ROLE OF BRCA1/AKT1 PATHWAY IN THE TUMORIGENESIS

描述(申请人提供)：乳腺癌易感基因1(BRCA1)在遗传性和散发性乳腺肿瘤发生中起关键作用。然而，BRCA1激活的分子通路对其肿瘤抑制活性的贡献程度仍不清楚。AKT激酶激活是与人类肿瘤相关的最常见的分子改变之一。据报道，在大多数乳腺癌中，AKT激酶活性增加。我们的初步数据表明，BRCA1表达下调或BRCA1基因突变激活了AKT1致癌途径。BRCA1直接与AKT1激酶结合，通过泛素化-蛋白质降解途径下调其激活。此外，AKT1突变体诱导的细胞生长依赖于它缺乏与BRCA1的相互作用。在人类乳腺癌中，BRCA1的表达减少与AKT1的磷酸化增加相关。这些结果支持这样的假设，即AKT1的激活参与了BRCA1缺陷介导的肿瘤发生。这些研究的具体目的是：(1)建立BRCA1-AKT1通路的分子细节；(2)了解BRCA1-AKT1通路在肿瘤发生中的作用；以及建立AKT1通路作为BRCA1缺陷性癌症的新的预防和治疗靶点。为了实现这些目标，计划进行一系列研究，这些研究将包括：1)确定BRCA1调控AKT1激活的分子机制并研究BRCA1与AKT1直接相互作用的功能效应；2)建立一个带有AKT1突变且无法与BRCA1相互作用的小鼠，并确定BRCA1-AKT1通路在肿瘤发生中的作用；3)靶向MTOR，AKT1的关键下游效应子，以确定AKT1途径是否是预防和治疗BRCA1缺陷癌症的新靶点。因此，在这一应用中拟议的研究将产生强有力的证据，证明AKT1激活在体内受到BRCA1的调节。Akt1突变小鼠模型将为研究BRCA1/AKT1通路在肿瘤发生和肿瘤治疗中的作用提供有用的新工具。

DESCRIPTION (provided by applicant): The breast cancer susceptibility gene 1 (Brca1) plays a key role in both hereditary and sporadic mammary tumorigenesis. However, the extent to which BRCA1-activated molecular pathways contribute to its tumor suppressor activity also remains unclear. Activation of AKT kinase is one of the most common molecular alterations associated with human tumors. Increased AKT kinase activity is reported in most of the breast cancers. Our preliminary data indicate that down-regulation of BRCA1 expression or mutations of the Brca1 gene activate the AKT1 oncogenic pathway. BRCA1 directly binds to AKT1 kinase and down-regulates its activation through the ubiquitination-protein degradation pathway. Moreover, the mutant of AKT1 induced the cell growth is dependent of that it lacks the interaction with BRCA1. In human breast cancers, reduced expression of BRCA1 is correlated with increased phosphorylation of AKT1. These results support the hypothesis that the activation of AKT1 is involved in BRCA1-deficiency mediated tumorigenesis. The specific aims of the proposed studies are: (1) To establish the molecular details of the BRCA1-AKT1 pathway; (2) To understand the contributions of BRCA1-AKT1 pathway to tumorigenesis; and to establish the AKT1 pathway as novel preventive and therapeutic targets for BRCA1-deficient cancers. To achieve these goals, a series of studies is planned which will: 1) Determine the molecular mechanism of BRCA1 regulating AKT1 activation and investigating the functional effects of the direct interaction of BRCA1 with AKT1; 2) Generate a knock-in mouse with AKT1 mutation that fails to interact with BRCA1 and define the role of BRCA1-AKT1 pathway in tumorigenesis; 3) Target mTOR, a critical downstream effector of AKT1, to determine whether the AKT1 pathway is a novel target for the prevention and treatment of BRCA1-deficient cancers. Thus, the proposed studies in this application will generate strong evidence that AKT1 activation is regulated by BRCA1 in vivo. The Akt1 mutant mouse model will be useful new tool for studies of the BRCA1/AKT1 pathway in tumorigenesis and cancer therapy.