Abstract BRCA1 and BRCA2 mutations (BRCA1 mut , BRCA2 mut ) increase the risk of breast cancer (BC) in women. The cumulative risk of developing breast cancer is estimated to be between 45-75% for carriers of BRCA1 mut and 41-70% for carriers of BRCA2 mut , compared to a population risk of about 13% in the USA. Although BRCA1 and BRCA2 were identified as breast cancer susceptibility genes nearly 30 years ago, many aspects of their functional roles in the development of specific types of breast cancer remain poorly understood. Both genes play a crucial role in repairing DNA double-strand breaks, but the types and characteristics of breast cancer associated with each gene differ. Patients with BRCA1 mut typically develop basal-like triple-negative breast cancer (TNBC), which is associated with poor survival rates. In contrast, patients with BRCA2 mut are more likely to develop luminal-like estrogen receptor-positive (ER+) breast cancer. To date, no applicable human breast tissue model systems are available for studying preneoplastic changes and neoplastic transformation elicited by variations in the underlying genetic and/or microenvironment risk factors, particularly for BRCA carriers. In this study, we aimed to elucidate the effects of germline BRCA1 mut and BRCA2 mut on breast cancer development. We also sought to identify the hormonal and somatic genetic factors that influence the initiation and progression of breast cancer in individuals with these mutations. To achieve this, we utilized a patient-specific, induced pluripotent stem cell (iPSC)-derived 3D mammary organoid model developed in our lab. iPSC technology and 3-dimensional (3D)-tissue engineering have provided opportunities to model human disease in vitro. This model system can self-renew and differentiate into multiple lineages and intrinsically self-organize to form 3D tissue architecture. Most importantly, tissue-derived iPSC from a specific individual harbors/retains both the genetic mutation and the whole genetic background of the patient. Several iPSC-derived, inherited disease models have been used to reproduce genetic mutation-associated high-risk cancers. These studies have revealed disease pathogenesis and carcinogenesis-initiating events in relevant human cell types. To model the risk of developing breast cancer associated with BRCA1/2 pathogenic variants, we generated three different BRCA1 mut and BRCA2 mut female iPSC cell lines and developed an iPSC-derived 3D mammary gland epithelium organoid model. Our initial study found that following differentiation into mammary gland organoids, both BRCA1 mut and BRCA2 mut heterozygous mutation carriers conferred a neoplastic phenotype reminiscent of a ductal carcinoma in situ(DCIS), a proposed precursor of BC (i.e., organoid models retained the wildtype copy of BRCA1 or BRCA2) compared to BRCA wildtype (BRCA1/2WT) controls, which retained both copies of both genes (confirmed by whole genome sequencing). Importantly, the development of DCIS in BRCA2 mut carriers is dependent on estrogen (E2) exposure, while in BRCA1 mut carriers, it is independent of hormonal influences. This indicates that BRCA haploinsufficiency contributes to the observed phenotype in both BRCA1 mut and BRCA2 mut carriers. Moreover, BRCA2 mut are more likely to lead to estrogen receptor-positive (ER+) breast cancer, while BRCA1 mut are associated with a higher risk of developing TNBC. Currently, we are expanding the BRCA1/2 iPSC lines cohort to generate mammary gland organoids with different BRCApathogenic variants and additional somatic alterations, aiming to estimate risk scores in developing BRCA1 mut versus BRCA2 mut breast cancer subtypes. Citation Format: N. Yucer, A. Okim, S. Dhungana, D. Bacich, K. Lawrenson, X. Cui, S. Gayther. Modeling of BRCA1/2 Breast Cancers Using iPSC Derived 3D Human Organoids Platform 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 PS3-03-29.
Yucer et al. (Tue,) studied this question.