Abstract PS1-13-02: Age-dependent mammary tumorigenesis in mice driven by the PIK3CA H1047R oncogene

Abstract The incidence of breast cancer increases with age. Hormone receptor positive (HR+) and HER2− tumor is the most prevalent subtype in older women. Approximately 70% of early-stage breast cancers (EBC) are HR+/HER2−, frequently harboring the PIK3CA H1047R mutation, which drives 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 the oncogenic potential of human PIK3CA H1047R across different age groups of FVB/NJ mice (young: 2 mo, n=10; middle-aged: 14 mo, n=8; aged: 22 mo, n=7) following intraductal injection of lentivirus-mediated PIK3CA H1047R expression. Mice were monitored for up to 6 months, and time to palpable tumor formation was used to generate tumor-free survival curves. qPCR was performed to assess PIK3CA H1047R genomic integration and gene expression. Ductal morphology and histopathology were evaluated using carmine whole-mount and hematoxylin and eosin staining. Morphometric analysis was performed using BD FACS Discover S8 Cell Sorter. High-dimensional flowcytometric analysis in FlowJo (t-SNE, FlowSOM, Cluster Explorer) was used to identify and characterize cell populations most susceptible to oncogenic transformation. Our results show that middle-aged and aged mice had significantly higher tumor incidence and developed tumors more rapidly than young mice, supported by higher PIK3CA H1047R integration and expression. Morphometric analysis revealed that luminal cells (CD49flowCD24high) expressed more PIK3CA H1047R than basal cells (CD49fhighCD24low). Importantly, epithelial cells from middle-aged and aged mice showed enrichment of a novel CD24+CD49f+ cell population with higher PIK3CA expression. The origin of these cells remains unclear and warrants further investigation. 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: T. Mohan, J. Mackay, M. McLaughlin, Y. Li, A. Nazarullah, L.-Z. Sun. Age-dependent mammary tumorigenesis in mice driven by the PIK3CA H1047R oncogene [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-13-02.