CORE D

摘要 APOBEC酶是单链DNA胞嘧啶到尿嘧啶脱氨酶，通常保护细胞免受 病毒感染。一个家族成员APOBEC3B(A3B)在超过一半的乳腺肿瘤中过度表达， 在20%的原发和50%的转移性乳腺肿瘤中发现了它的突变特征。A3B过度表达 和突变特征也与治疗失败和总体存活率低有关。我们的节目 研究表明，抑制A3B介导的肿瘤演变有助于改善A3B患者的治疗结果 雌激素受体阳性乳腺癌小鼠模型的建立。这些数据支持我们的计划的统一 假设A3B抑制作为主要治疗选择的辅助，将有助于防止有害的 突变驱动的结果，如耐药性和转移。我们的计划成员正在合作 通过三个紧密结合的项目来检验这一假设，这些项目集中在生物学、化学生物学和 A3B的结构生物学。这些项目得到了4个服务核心的支持，包括核心D-酵素和 抗体，有两个特定的目的：目标1是产生重组APOBEC酶并执行 用这些酶进行标准DNA脱氨酶分析，这将使APOBEC研究标准化 跨越实验室和时间。目的2是研制针对A3B及相关人类的特异性单抗 APOBEC3酶。特定抗体的出现将推动该计划的研究，并正在 这对该计划的翻译目标很重要，即开发一种基于抗体的检测方法来诊断A3B阳性肿瘤，以便告知患者的预后，并最终确定治疗计划。由此产生的试剂 这两个目标对于加快每个项目的目标至关重要，确保最大限度的严谨性和可重复性 跨项目和协作实验室，推动计划协作和APOBEC研究 更大的癌症研究社区。总体而言，尽管核心D的规模相对较小，但它是一个强大的使能 我们节目的特色。

ABSTRACT APOBEC enzymes are single-stranded DNA cytosine-to-uracil deaminases that normally protect cells from viral infections. One family member, APOBEC3B (A3B), is overexpressed in over half of all breast tumors and its mutation signature is found in 20% of primary and 50% of metastatic breast tumors. A3B overexpression and mutation signature have also been associated with therapy failure and poor overall survival. Our Program has shown that inhibition of A3B-mediated tumor evolution contributes to improved therapy outcomes in a mouse model of estrogen receptor-positive breast cancer. These data support our Program’s unifying hypothesis that A3B inhibition, as an adjuvant to primary treatment options, will help to prevent detrimental mutation-driven outcomes such as drug resistance and metastasis. Our Program members are collaborating to test this hypothesis through 3 tightly integrated Projects focusing on the biology, chemical biology, and structural biology of A3B. These Projects are supported by 4 service Cores, including Core D – Enzymes & Antibodies, which has 2 specific aims: Aim 1 is to produce recombinant APOBEC enzymes and to perform standard DNA deaminase assays with these enzymes, which will allow standardization of APOBEC studies across labs and time. Aim 2 is to develop specific monoclonal antibodies for A3B and related human APOBEC3 enzymes. The availability of specific antibodies will move the Program’s research forward and is important for the Program’s translational goal of developing an antibody-based assay for diagnosing A3Bpositive tumors in order to inform patient prognosis and, ultimately, therapeutic plans. The reagents resulting from both Aims are vital for expediting the goals of each Project, ensuring maximal rigor and reproducibility across Projects and collaborating labs and fueling Program collaborations and APOBEC research in the greater cancer research community. Overall, despite its relatively modest size, Core D is a powerful enabling feature of our Program.