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.

乳腺癌中的载脂蛋白突变

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

Clinical Implications of APOBEC3-Mediated Mutagenesis in Breast Cancer.

• DOI: 10.1158/1078-0432.ccr-22-2861
• 发表时间: 2023-05-01
• 期刊: CLINICAL CANCER RESEARCH
• 影响因子: 11.5
• 作者: Roelofs, Pieter A.;Martens, John W. M.;Harris, Reuben S.;Span, Paul N.
• 通讯作者: Span, Paul N.

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