Abstract 1384: Aging amplifies oncogenic mutant pik3ca 1047R signaling and accelerates mammary tumorigenesis.

Abstract Breast cancer incidence increases with age, and hormone receptor positive (HR+) and HER2 negative tumors represents the most prevalent subtype among older women. Approximately 70% of early-stage breast cancers are HR+/HER2−, frequently harboring the PIK3CA H1047R mutation, a driver of heterogeneous mammary carcinomas. Understanding how PIK3CA H1047R mutant interacts with the aging microenvironment is important for elucidating age-related susceptibility and may enlighten age-specific therapeutic strategies. In this study, we investigated age-dependent susceptibility to PIK3CA H1047R-driven tumorigenesis using intraductal delivery of lentivirus expressing human PIK3CA H1047R in FVB/NJ mice across three age groups (young: 2 mo, n=10; middle-aged: 14 mo, n=8; aged: 22 mo, n=7). Mice were monitored for up to 6 months, and the time to palpable tumor formation was used to generate tumor-free survival curves. qPCR analysis confirmed age-dependent differences in PIK3CA H1047R genomic integration and expression. Ductal morphology and histopathology were evaluated using carmine whole-mount and hematoxylin and eosin staining. Morphometric characterization was performed using BD FACS Discover S8 Cell Sorter. High-dimensional flowcytometric analysis (t-SNE, FlowSOM, Cluster Explorer) was used to identify epithelial subsets most susceptible to transformation. Middle-aged and aged mice displayed significantly higher tumor incidence and shorter latency compared with young mice, consistent with increased PIK3CA integration and expression. Morphometric analysis revealed that luminal cells (CD49flowCD24high) expressed maximal PIK3CA H1047R protein concentration (Max Intensity MFI) than basal cells (CD49fhighCD24low). Further, Eccentricity and Radial movement imaging features revealed age- and lineage-specific oncogenic responses. Together, these findings indicate that aging is not merely a risk factor but actively modifies PIK3CA-driven oncogenic signaling. These age-associated alterations in mammary epithelial cell populations may inform development of targeted therapies for older patients with HR+/HER2− breast cancer. A limitation of this study is the use of a murine intraductal model, which may not fully capture human breast cancer biology. Further studies incorporating stromal and immune components are needed to comprehensively understand how aging influences oncogenic PIK3CA signaling. Citation Format: Thangarajeswari Mohan, Jacob Mackay, Morgana McLaughlin, Yue Li, Alia Nazarullah, Lu-Zhe Sun, . Aging amplifies oncogenic mutant pik3ca 1047R signaling and accelerates mammary tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1384.