Abstract 2409: Examining APOBEC3B in TCGA and ICGC breast cancer datasets reveals altered drug metabolism pathways
Authors: Joel Pardo, Nuri Temiz, Douglas Yee
Journal: Cancer Research (2025)

Abstract Despite advancements in screening and treatment, breast cancer mortality remains significant, with nearly one-third of patients worldwide succumbing to the disease. APOBECs, a large family of cytosine deaminase enzymes, function endogenously to restrict viral replication. However, their upregulation in many cancers has been linked to a distinct mutational signature characterized by cytosine-to-uracil conversions, leading to C-to-T transitions. Among these enzymes, APOBEC3B (A3B) is notably overexpressed in breast cancer. It remains uncertain, however, whether tumors with an enriched A3B mutational signature consistently exhibit elevated A3B expression across different breast cancer subtypes. Studies estimate the A3B mutational signature is present in 30-50% of breast cancer cases, with higher prevalence in triple-negative breast cancer (TNBC) and HER2-enriched subtypes. Understanding the pathways influencing A3B expression is an area of growing research interest. Using DNA and RNA sequencing data from breast cancer patients in The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), we observed that over 64% of tumors with enriched A3B genomic mutational signatures exhibited above-median A3B mRNA expression compared to non-enriched tumors (p &amp;lt; 0.001). Pathway analyses, including KEGG, Gene Ontology (GO), and Reactome, of high versus low A3B-expressing tumors revealed associations with pathways involved in tumor drug metabolism. Notably, the tamoxifen regulatory pathway was altered in high A3B-expressing tumors, which showed reduced expression of CYP2D6 and CYP3A10. This downregulation was consistent in luminal-A-like and luminal-B-like samples. Previous studies in mouse model systems have demonstrated diminished responses to tamoxifen in cells with high A3B expression; our findings suggest a potential relationship between high A3B expression and altered tamoxifen metabolism through CYP2D6. Additionally, pathways related to uracil synthesis, involving drugs such as 5-fluorouracil and 6-mercaptopurine, were downregulated in tumors with high A3B expression. Downregulated genes included IMPDH1, NME1, TK1, and DPYS, many of which are directly associated with pyrimidine synthesis. This pattern of downregulation was consistent across luminal-A-like, luminal-B-like, and basal-like breast cancer subtypes. These findings suggest that tumors with elevated A3B expression may have a heightened ability to develop resistance to therapies such as tamoxifen. Conversely, such tumors might exhibit increased susceptibility to treatments like 5-fluorouracil. Evaluating the functional consequences of A3B expression in breast cancers could pave the way for strategies to modulate A3B activity, enhancing the efficacy of existing therapies and mitigating drug resistance. Citation Format: Joel Pardo, Nuri Temiz, Douglas Yee. Examining APOBEC3B in TCGA and ICGC breast cancer datasets reveals altered drug metabolism pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2409.