APOBEC MUTAGENESIS IN BREAST CANCER

乳腺癌中的 APOBEC 突变

• 批准号: 10474974
• 负责人: Reuben S Harris
• 金额: $ 175.12万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-09 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10474974
• 关键词: Address; Aging; Antibodies; Binding; Biological Assay; Biological Models; Biology; Biophysics; Breast Cancer Cell; Cell physiology; Cells; Chemicals; Chromosomal Rearrangement; Clinical; Complex; Cytosine; Cytosine deaminase; DNA; DNA Repair Enzymes; DNA Transposable Elements; Data; Deamination; Defect; Development; Diagnosis; Disease; Disease Progression; Disease Resistance; Drug resistance; Enzymes; Estrogen receptor positive; Family; Foundations; Genomics; Goals; Inherited; Knowledge; Lead; Leadership; Lesion; Malignant Neoplasms; Mammary Neoplasms; Metastatic breast cancer; Mission; Molecular; Monoclonal Antibodies; Mutagenesis; Mutation; Neoplasm Metastasis; Nucleic Acids; Oncoproteins; Outcome; PIK3CA gene; Patients; Persons; Primary Lesion; Primary Neoplasm; Process; Proteins; Publishing; Reagent; Recurrence; Recurrent disease; Regulation; Reporter; Reporting; Research; Research Project Grants; Residual state; Resistance; Scientific Advances and Accomplishments; Services; Single-Stranded DNA; Site; Source; System; Techniques; Testing; The Cancer Genome Atlas; Therapeutic; Time; Uracil; Virus Replication; Water; Woman; Work; antibody diagnostic; anticancer research; base; biophysical techniques; brca gene; cancer recurrence; clinical care; clinical translation; computational chemistry; computerized tools; diagnostic assay; ds-DNA; experience; homologous recombination; improved; inhibitor; innovation; interdisciplinary approach; malignant breast neoplasm; member; molecular recognition; mouse model; multidisciplinary; new technology; novel; novel diagnostics; overexpression; preference; prevent; programs; repaired; small molecule; structural biology; technology development; therapy outcome; therapy resistant; tumor; tumor heterogeneity; tumor progression

OVERALL – APOBEC MUTAGENESIS IN BREAST CANCER ABSTRACT APOBEC signature mutations make up 20% of base-substitution mutations in primary tumors, which increases to over 50% in metastases. Additional enrichment is often observed in estrogen receptor (ER)- positive disease. APOBEC-catalyzed C-to-U lesions in single-stranded (ss)DNA lead to signature C-to-T and C-to-G mutations within 5′-TCA and 5′-TCT trinucleotide motifs. In addition, APOBEC-derived C-to-U lesions can be (mis)processed by cellular DNA repair enzymes, resulting in single- and double-stranded DNA breaks and more complex chromosomal rearrangements. APOBEC expression levels and mutagenesis correspond with poor clinical outcomes, such as shorter disease-free and overall survival in women with operable ER- positive breast cancer. Elevated APOBEC levels also predict poor overall survival for patients diagnosed with recurrent ER-positive metastases. These and other published data demonstrate that APOBEC mutagenesis is ongoing in breast tumor cells and underpin our overarching Program hypothesis that inhibiting APOBEC will prevent a large proportion of additional mutations from happening in residual ER-positive disease and will thereby improve the durability of current treatments and result in better overall therapeutic outcomes. Three multidisciplinary Projects will work together in an integrated and comprehensive manner to test this idea. Project 1 will develop reporter systems for quantifying APOBEC activity in living cells and determine the molecular mechanisms responsible for APOBEC regulation and for genomic uracil processing in breast cancer cells. Project 2 will use chemical biology approaches to investigate the mechanism of APOBEC-catalyzed ssDNA deamination and will develop nucleic acid and small molecule probes to inhibit APOBEC activity. Project 3 will leverage structural and biophysical approaches to investigate global mechanisms for APOBEC binding to ssDNA as well as the local structural features important for target sequence preferences and inhibition of APOBEC enzymes in breast cancer. These Projects will be supported by service Cores for administration, murine models, computational chemistry and biophysics, and enzymes and antibodies. Our Program is poised to have both immediate and long-term impact for ER-positive breast cancer: immediate impact by producing novel technologies and a comprehensive understanding of the mechanism of APOBEC mutagenesis, and long-term impact on clinical translation through the development of technologies for diagnosing APOBEC-positive disease and the creation of novel chemical matter to inhibit this mutational process for therapeutic benefit.

总体而言——乳腺癌中的 APOBEC 突变 抽象的 APOBEC 特征突变占原发性肿瘤碱基取代突变的 20%， 在转移瘤中经常观察到雌激素受体 (ER) 的额外富集。 APOBEC 催化的单链 (ss)DNA 中的 C-to-U 损伤导致特征性 C-to-T 和 5'-TCA 和 5'-TCT 三核苷酸基序内的 C 至 G 突变此外，APOBEC 衍生的 C 至 U 病变。 可以被细胞 DNA 修复酶（错误）处理，导致单链和双链 DNA 断裂 以及更复杂的染色体重排与 APOBEC 表达水平和诱变相对应。 临床结果较差，例如可手术 ER 女性的无病生存期和总生存期较短 APOBEC 水平升高也预示着乳腺癌患者的总生存期较差。 这些和其他已发表的数据表明 APOBEC 突变是复发性 ER 阳性转移。 乳腺肿瘤细胞中正在进行的研究，并支持我们的总体计划假设，即抑制 APOBEC 将 防止残余 ER 阳性疾病中发生很大一部分额外突变，并将 从而提高当前治疗的持久性并产生更好的整体治疗结果。 多学科项目将以综合全面的方式共同努力来测试这一想法。 项目 1 将开发用于量化活细胞中 APOBEC 活性的报告系统，并确定 乳腺癌中负责 APOBEC 调节和基因组尿嘧啶加工的分子机制 项目2将使用化学生物学方法来研究APOBEC催化的机制。 ssDNA 脱氨基，并将开发核酸和小分子探针来抑制 APOBEC 活性。 项目 3 将利用结构和生物物理方法来研究 APOBEC 的全球机制 与 ssDNA 的结合以及对目标序列偏好很重要的局部结构特征 这些项目将得到服务核心的支持。 管理、小鼠模型、计算化学和生物物理学以及酶和抗体。 该计划有望对 ER 阳性乳腺癌产生直接和长期影响：立即 产生新技术的影响和对 APOBEC 机制的全面理解 诱变以及通过技术开发对临床转化的长期影响 诊断 APOBEC 阳性疾病并创造新的化学物质来抑制这种突变 治疗效果的过程。