Abstract Germline mutations in BRCA1 significantly increase the risk of BRCA1 (+/-) heterozygous carriers in developing early and rapid breast and ovarian cancers. However, the physiological alterations in heterozygous BRCA1 (+/-) breast tissue necessary for malignant transformation, and the specific features predisposing this tissue to loss of heterozygosity (LOH) are poorly understood. BRCA1 (+/-) carrier breast tissue is reported to contain a small population of cells with copy number alterations (CNAs) (1q gain and 16q loss), p53 mutations, and LOH of BRCA1. A previous study showed that BRCA1 (+/-) carrier breast tissue fibroblasts and mammary epithelial cell lines have several features of replication stress (R/S), which may contribute to genomic instability and progression to cancer. Luminal progenitor cells (LPs) appear to be the primary cells leading to these cancers but the contribution of other subpopulations in breast tissue remains to be elucidated. Patient-derived BRCA1 (+/-) carrier organoids are a living, physiological system that allows for this study of R/S, BRCA1 LOH, and acquired CNAs in all breast subpopulations in parallel. To further examine the phenotype of BRCA1 (+/-) breast tissue, we generated viably-growing carrier organoids derived from breast tissues of seventeen BRCA1 (+/-) women, who underwent prophylactic mastectomy, and from fifteen BRCA1 (+/+) women who underwent reduction surgery as controls. Hydroxyurea induced R/S, as indicated by increased levels of pKAP1, yH2AX, and ELF3, in all subpopulations of the BRCA1 (+/-) carrier organoids in comparison to the BRCA1 (+/+) organoids. Consequently, BRCA1 (+/-) carrier breast tissues and organoids exhibited shortened telomere length and high levels of ELF5, a premature aging marker, suggesting that BRCA1 (+/-) carriers are predisposed to altered telomere replication leading to R/S. BRCA1 (+/-) carrier organoids and tissues are enriched for G2/M markers where homologous recombination (HR) is a critical DNA damage pathway that resolves R/S. A BRCA1 (+/-) carrier with PARPi sensitivity, indicative of HR deficiency, exhibited some of the common CNAs previously detected in BRCA1 (-/-) breast tumors (1q gain and 16q loss) suggesting LOH in small fraction of cells. Overall, patient-derived organoid models allow for the evaluation of the BRCA1 (+/-) pathologic phenotype and testing drugs for preventing the outgrowth of BRCA1 (-/-) malignant clones. Acknowledgments: We’d like to thank to patients for donating tissue, as well as Alicia Pollaci (CTO Sr Research Project Mgr) and Claire Capaldi (Research Lab Tech) for helping on the tissue collections. In addition, we would like to thank MacLean C. Sellars MD, PhD for the flow cytometry analysis. Citation Format: O. Somuncu, B. Lamarre, S. Mukkavalli, T. B. Branigan, R. Ravindranathan, N. V. Wietmarschen, H. Nguyen, N. Ashton, K. Parmar, G. Shapiro, D. A. Dillon, D. Chowdhury, P. A. Konstantinopoulos, J. E. Garber, A. D. D'Andrea. Replication stress as a driver of breast tumorigenesis in BRCA1 heterozygous carrier derived breast organoids 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 PS3-01-25.
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