ROLE OF BRCA1/AKT1 PATHWAY IN THE TUMORIGENESIS

BRCA1/AKT1 通路在肿瘤发生中的作用

• 批准号: 8193157
• 负责人: Qin Yang
• 金额: $ 30.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193157
• 关键词: AKT1 gene; BRCA1 gene; BRCT Domain; Binding; Breast Cancer Prevention; Cancer-Predisposing Gene; Carcinogens; Cell Cycle; Cell Proliferation; Chromosomal Instability; Data; Defect; Degradation Pathway; Development; Down-Regulation; Genes; Goals; Health; Human; Inherited; Knock-in Mouse; Malignant Neoplasms; Mammary Neoplasms; Mammary Tumorigenesis; Mediating; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Oncogenic; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Predisposing Factor; Prevention; Preventive; Protein Isoforms; Proto-Oncogene Proteins c-akt; Radiation-Induced Cancer; Regulation; Reporting; Role; Series; Sirolimus; Site; Testing; Tumor Suppressor Proteins; Ubiquitination; base; cancer prevention; cancer therapy; cell growth; chemotherapeutic agent; improved; in vivo; mTOR protein; malignant breast neoplasm; mutant; mutant mouse model; novel; protein degradation; therapeutic target; tool; tumor; tumorigenesis

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.

描述（由申请人提供）：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激活的分子途径在多大程度上促进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。AKT激酶活性的增加在大多数乳腺癌中都有报道。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直接结合AKT1激酶，通过泛素化-蛋白降解途径下调其活化。此外，AKT1突变体诱导细胞生长是依赖于它缺乏与BRCA1的相互作用。在人类乳腺癌中，BRCA1表达的减少与AKT1磷酸化的增加相关。这些结果支持了AKT1的激活参与brca1缺陷介导的肿瘤发生的假设。拟建研究的具体目的是：(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；并建立AKT1通路作为brca1缺陷癌症的新的预防和治疗靶点。为了实现这些目标，我们计划开展一系列研究，包括：1)确定BRCA1调控AKT1激活的分子机制，研究BRCA1与AKT1直接相互作用的功能效应；2)生成不能与BRCA1相互作用的AKT1突变敲入小鼠，明确BRCA1-AKT1通路在肿瘤发生中的作用；3)靶向AKT1的关键下游效应物mTOR，确定AKT1通路是否为预防和治疗brca1缺陷型癌症的新靶点。因此，本应用中提出的研究将提供强有力的证据，证明AKT1激活在体内受BRCA1调节。Akt1突变小鼠模型将为BRCA1/ Akt1通路在肿瘤发生和癌症治疗中的研究提供有用的新工具。公共卫生相关性：在癌症发展中建立新的BRCA1-AKT1通路，并阐明其精确的分子功能，有望提高我们对遗传性和散发性癌症形成的理解。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。