FBX044 mediated BRCA1 degradation in sporadic breast cancers

FBX044 介导散发性乳腺癌中 BRCA1 降解

• 批准号: 8787951
• 负责人: YANFEN HU
• 金额: $ 16.06万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787951
• 关键词: Accounting; BRCA1 Protein; BRCA1 gene; Breast; Breast Cancer Cell; Breast Cancer Treatment; Cancer Etiology; Cancer-Predisposing Gene; Cell Cycle Checkpoint; Cell Proliferation; Cells; DNA Double Strand Break; DNA Repair; Development; Double Strand Break Repair; Ectopic Expression; Etiology; Event; Genes; Genome Stability; Genomic Instability; Germ-Line Mutation; Growth; Health; Hereditary Breast Carcinoma; Hypermethylation; In Vitro; Lead; Length; Light; Malignant Neoplasms; Mammary Neoplasms; Mediating; Pathway interactions; Peptides; Physiological; Play; Prognostic Marker; Proteins; Reporting; Role; Small Interfering RNA; Somatic Mutation; Stem cells; Testing; Therapeutic; Therapeutic Agents; Tumor Suppressor Proteins; Ubiquitination; Work; base; cancer cell; cancer therapy; cell growth; in vivo; insight; malignant breast neoplasm; migration; multicatalytic endopeptidase complex; neoplastic cell; novel; novel therapeutics; ovarian neoplasm; progenitor; promoter; protein degradation; research study; targeted treatment; therapeutic target; tool; tumor; tumor growth; tumorigenesis; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): BRCA1 functions as a breast/ovarian tumor suppressor by promoting high fidelity DNA repair and maintaining genome stability. While germline mutations of BRCA1 account for approximately 50% of familial breast cancer cases, somatic mutations of the gene are rarely found in sporadic breast cancer. Rather, a large number of invasive sporadic breast tumors express wild-type BRCA1 protein at relatively low levels, raising the possibility that BRCA1 may also contribute to sporadic breast cancer development and progression. Given that sporadic breast cancers constitute approximately 90-95% of all breast cancer cases, understanding of the underlying mechanism by which BRCA1 expression is deregulated in sporadic cancer is highly significant and promises to have a broad impact on breast cancer etiology and treatment. Our preliminary work leads to the discovery of FBXO44, a key component of the SCFFBXO44 ubiquitin E3 ligase, that directly ubiquitinates BRCA1 and triggers its proteasome-mediated degradation in breast cancer cells. Importantly, FBXO44 is expressed at high levels in 90% of sporadic breast cancer with low BRCA1 expression. The objective of this application is to validate the hypothesis that aberrant expression of SCFFBXO44 results in reduced BRCA1 protein stability, which in turn leads to impaired DSB DNA repair and more aggressive tumor growth. To test this central hypothesis, we will examine the impact of FBXO44 on BRCA1 functions in DNA double-strand break repair, cell cycle checkpoint control, and tumor migration and invasion. In addition, we will seek to develop a pathway-specific tool to restore BRCA1 protein levels in sporadic cancer cells. When accomplished, the proposed work promises to elucidate a previously unappreciated mechanism of deregulated BRCA1 expression in sporadic cancer and inform development of novel therapeutic agents for sporadic breast cancer with low BRCA1 expression.

描述（申请人提供）：BRCA 1通过促进高保真DNA修复和维持基因组稳定性发挥乳腺/卵巢肿瘤抑制因子的作用。虽然BRCA 1的种系突变约占家族性乳腺癌病例的50%，但该基因的体细胞突变在散发性乳腺癌中很少发现。相反，大量侵袭性散发性乳腺肿瘤以相对低的水平表达野生型BRCA 1蛋白，这增加了BRCA 1也可能有助于散发性乳腺癌发展和进展的可能性。鉴于散发性乳腺癌约占所有乳腺癌病例的90-95%，了解BRCA 1表达在散发性癌症中失调的潜在机制非常重要，并有望对乳腺癌病因学和治疗产生广泛影响。 我们的初步工作导致FBXO 44的发现，FBXO 44是SCFFBXO 44泛素E3连接酶的关键组分，直接泛素化BRCA 1并触发其在乳腺癌细胞中的蛋白酶体介导的降解。重要的是，FBXO 44在90%的散发性乳腺癌中以高水平表达，而BRCA 1表达较低。本申请的目的是验证SCFFBXO 44的异常表达导致BRCA 1蛋白稳定性降低的假设，这反过来又导致DSB DNA修复受损和更具侵袭性的肿瘤生长。为了验证这一中心假设，我们将研究FBXO 44对BRCA 1在DNA双链断裂修复、细胞周期检查点控制以及肿瘤迁移和侵袭中功能的影响。此外，我们将寻求开发一种途径特异性工具来恢复散发性癌细胞中的BRCA 1蛋白水平。一旦完成，拟议的工作有望阐明散发性癌症中BRCA 1表达失调的先前未被认识到的机制，并为BRCA 1低表达的散发性乳腺癌的新型治疗药物的开发提供信息。