FBX044 mediated BRCA1 degradation in sporadic breast cancers

FBX044 介导散发性乳腺癌中 BRCA1 降解

• 批准号: 8623171
• 负责人: YANFEN HU
• 金额: $ 19.32万
• 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 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8623171
• 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; 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; public health relevance; research study; therapeutic target; tool; tumor; tumor growth; tumorigenesis; ubiquitin-protein ligase

ABSTRACT 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.

摘要 BRCA 1通过促进高保真度作为乳腺/卵巢肿瘤抑制因子发挥作用 DNA修复和维持基因组稳定性。虽然BRCA 1的生殖系突变 占家族性乳腺癌病例的约50%， 基因在散发性乳腺癌中很少发现。相反，大量的侵入性 散发性乳腺肿瘤以相对低的水平表达野生型BRCA 1蛋白， BRCA 1也可能促进散发性乳腺癌发展 和进步。鉴于散发性乳腺癌约占90-95%， 在所有乳腺癌病例中，了解BRCA 1 在散发性癌症中表达失调是非常重要的，并有望产生一种新的癌症。 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了FBXO 44的发现，FBXO 44是 SCFFBXO 44泛素E3连接酶，直接泛素化BRCA 1并触发其 乳腺癌细胞中蛋白酶体介导的降解。重要的是，FBXO 44是 BRCA 1在90%的散发性乳腺癌中高水平表达，而BRCA 1表达较低。 本申请的目的是验证以下假设： SCFFBXO 44导致BRCA 1蛋白稳定性降低，这反过来又导致BRCA 1蛋白稳定性受损。 DSB DNA修复和更具侵略性的肿瘤生长。为了验证这一假设，我们 将研究FBXO 44对BRCA 1在DNA双链断裂中功能的影响 修复、细胞周期检查点控制以及肿瘤迁移和侵袭。另外我们 将寻求开发一种途径特异性工具，以恢复散发性乳腺癌患者的BRCA 1蛋白水平。 癌细胞完成后，拟议的工作承诺阐明以前的 散发性癌症中BRCA 1表达失调的未被认识的机制， 散发性低分化乳腺癌新治疗药物进展 BRCA 1表达。