APOBEC MUTAGENESIS IN BREAST CANCER

乳腺癌中的 APOBEC 突变

• 批准号: 10738334
• 负责人: Reuben S Harris
• 金额: $ 8.05万
• 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/10738334
• 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 Double Strand Break; 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; Nucleotides; Oncoproteins; Outcome; PIK3CA gene; Patients; Persons; Primary Lesion; Primary Neoplasm; Process; Proteins; Publishing; Reagent; Recurrence; Recurrent Malignant Neoplasm; 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; 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 - 乳腺癌中的APOBEC诱变 抽象的 APOBEC签名突变占原发性肿瘤中基本替代突变的20％，这些突变是 转移酶中增加到50％以上。在雌激素受体（ER） - 阳性疾病。单链（SS）DNA中的APOBEC催化的C-TO-U病变导致签名C-TO-T和 5'-TCA和5'-TCT三核苷酸基序中的C-G突变。此外，APOBEC衍生的C-TO-U腿 可以通过细胞DNA修复酶（MIS）处理，从而导致单链DNA断裂 以及更复杂的染色体重排。 APOBEC表达水平和诱变相对应 临床结果不佳，例如无病的较短和可操作的ER-女性的总体存活率 阳性乳腺癌。 APOBEC水平升高还可以预测，诊断为患者的总体生存率差 复发性ER阳性转移。这些和其他已发表的数据表明，apobec诱变是 在乳腺肿瘤细胞中持续的持续和基础我们的总体计划假设，即抑制APOBEC将会 防止在残留ER阳性疾病中发生大量其他突变，并将 从而提高了当前治疗的耐用性，并带来更好的总体治疗结果。三 多学科项目将以综合而全面的方式一起测试这一想法。 项目1将开发记者系统，以量化活细胞中的APOBEC活性并确定 负责APOBEC调节和乳腺癌基因组加工的分子机制 细胞。项目2将使用化学生物学方法研究APOBEC催化的机制 ssDNA脱氨基将出现核酸和小分子问题以抑制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结合以及局部结构特征对于目标序列偏好和 抑制乳腺癌中APOBEC酶。这些项目将得到服务核心的支持 给药，鼠模型，计算化学和生物物理学以及酶和抗体。我们的 计划中毒，对ER阳性乳腺癌产生直接和长期影响：立即 通过生产新技术和对APOBEC机制的全面理解来影响 诱变，以及对临床翻译的长期影响，通过开发技术 诊断APOBEC阳性疾病和创建新型化学物质以抑制这种突变 治疗益处的过程。

项目成果

Disease-related mutations in PI3Kγ disrupt regulatory C-terminal dynamics and reveal a path to selective inhibitors.

• DOI: 10.7554/elife.64691
• 发表时间: 2021-03-04
• 期刊: eLife
• 影响因子: 7.7
• 作者: Rathinaswamy MK;Gaieb Z;Fleming KD;Borsari C;Harris NJ;Moeller BE;Wymann MP;Amaro RE;Burke JE
• 通讯作者: Burke JE

Aberrant APOBEC3B Expression in Breast Cancer Is Linked to Proliferation and Cell Cycle Phase.

• DOI: 10.3390/cells12081185
• 发表时间: 2023-04-18
• 期刊: CELLS
• 影响因子: 6
• 作者: Roelofs, Pieter A. A.;Timmermans, Mieke A. M.;Stefanovska, Bojana;den Boestert, Myrthe A. A.;van den Borne, Amber W. M.;Balcioglu, Hayri E. E.;Trapman, Anita M. M.;Harris, Reuben S. S.;Martens, John W. M.;Span, Paul N. N.
• 通讯作者: Span, Paul N. N.

Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer.

• DOI: 10.1038/s41388-022-02235-8
• 发表时间: 2022-04
• 期刊: Oncogene
• 影响因子: 8
• 作者: Baker SC;Mason AS;Slip RG;Skinner KT;Macdonald A;Masood O;Harris RS;Fenton TR;Periyasamy M;Ali S;Southgate J
• 通讯作者: Southgate J

Differentiation signals induce APOBEC3A expression via GRHL3 in squamous epithelia and squamous cell carcinoma

分化信号通过 GRHL3 在鳞状上皮和鳞状细胞癌中诱导 APOBEC3A 表达

• DOI: 10.21203/rs.3.rs-3997426/v1
• 发表时间: 2024
• 作者: Fenton T

Acute expression of human APOBEC3B in mice results in RNA editing and lethality.

• DOI: 10.1186/s13059-023-03115-4
• 发表时间: 2023-11-24
• 期刊: Genome biology
• 影响因子: 12.3