CORE D

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CORE D – ENZYMES & ANTIBODIES 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 A3B- positive 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.