ROLE OF BRCA1/AKT1 PATHWAY IN THE TUMORIGENESIS

描述（申请人提供）：乳腺癌易感基因1（Brca 1）在遗传性和散发性乳腺肿瘤发生中起关键作用。然而，BRCA 1激活的分子通路在多大程度上有助于其肿瘤抑制活性仍不清楚。AKT激酶的激活是与人类肿瘤相关的最常见的分子改变之一。据报道，大多数乳腺癌中AKT激酶活性增加。我们的初步数据表明，下调BRCA 1表达或突变的Brca 1基因激活AKT 1致癌途径。BRCA 1直接与AKT 1激酶结合，并通过泛素化蛋白降解途径下调其活化。此外，AKT 1突变体诱导的细胞生长依赖于它缺乏与BRCA 1的相互作用。在人类乳腺癌中，BRCA 1表达减少与AKT 1磷酸化增加相关。这些结果支持AKT 1的激活参与BRCA 1缺陷介导的肿瘤发生的假设。这些研究的具体目的是：（1）建立BRCA 1-AKT 1通路的分子细节;（2）了解BRCA 1-AKT 1通路在肿瘤发生中的作用;并建立AKT 1通路作为BRCA 1缺陷癌症的新的预防和治疗靶点。为了实现这些目标，我们计划进行一系列的研究：1）确定BRCA 1调节AKT 1活化的分子机制，并研究BRCA 1与AKT 1直接相互作用的功能效应; 2）产生AKT 1突变的敲入小鼠，其不能与BRCA 1相互作用，并确定BRCA 1-AKT 1通路在肿瘤发生中的作用; 3）靶向AKT 1的关键下游效应子mTOR，以确定AKT 1通路是否是预防和治疗BRCA 1缺陷型癌症的新靶点。因此，本申请中提出的研究将产生强有力的证据，证明AKT 1激活在体内受BRCA 1调节。Akt 1突变小鼠模型将为研究BRCA 1/AKT 1通路在肿瘤发生和肿瘤治疗中的作用提供新的工具。公共卫生相关性：建立新的BRCA 1-AKT 1通路在癌症发展和阐明其精确的分子功能，预计将提高我们的理解遗传性以及散发性癌症的形成。申请中提出的研究应对乳腺癌预防和治疗领域做出重大贡献。

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. PUBLIC HEALTH RELEVANCE: Establishment of the novel BRCA1-AKT1 pathway in cancer development and elucidation of its precise molecular functions are expected to improve our understanding of hereditary as well as sporadic cancer formation. The studies proposed in the application should make significant contributions to the field of breast cancer prevention and therapy.