Abstract Background: Invasive lobular carcinoma (ILC) is the most common special histologic subtype of breast cancer, accounting for 8-14% of cases. Nearly 95% of ILCs are estrogen receptor positive (ER+) and managed with endocrine therapy. However, optimal rodent models are limited for studying ILC evolution and therapeutic vulnerabilities. Although mouse ILC models have been generated by mutating CDH1 (which encodes E-cadherin), a hallmark of ILC, but these tumors rarely show estrogen dependence. Rats, which have mammary biology more similar to humans, can easily generate ER+ and estrogen-dependent tumors. Our lab has successfully established ER+, estrogen-dependent ductal tumors in rats using intraductal CRISPR/Cas9 editing. Here, we aim to develop a rat model of ILC by targeting CDH1 and PIK3CA, the most frequently mutated driver in human breast cancer. Methods: AAV-sgRNA constructs targeting CDH1 and activating PIK3CAH1047R were delivered intraductally to induce somatic CDH1 loss and PIK3CA activation in rat mammary epithelial cells and drive tumor formation. Results: AAV targeting CDH1 (AAV-C) efficiently induced knockout in Cas9-expressing rat primary cells in vitro, and deep sequencing confirmed high editing rates. Intraductal delivery of AAV inducing CDH1 loss and PIK3CAH1047R activation (AAV-rPC) generated tumors with a latency of 2-3 months, significantly shorter than tumors induced by AAV-PIK3CAH1047R alone (AAV-rP, ∼4 months). Importantly, AAV-C alone did not induce tumors in the rat mammary gland, and AAV-rP did not generate lobular lesions. Somatic CDH1 knockout combined with PIK3CAH1047R activation efficiently induced widespread LCIS and ILC. Mammary tumors induced by AAV-rPC were characterized by high ER and progesterone receptor (PR) expression with moderate Ki67 and were hormone-dependent. Ongoing studies are profiling tumor transcriptomes and immune features and comparing them with human ILCs. Conclusion: CRISPR/Cas9-mediated targeting of CDH1 and PIK3CA in rats produces a clinically relevant ER+ ILC model. Citation Format: Yuxiang Lin, Luyu Jia, Derrick Manosh Thomas, Wen Bu, Carolina Gutierrez, Yi Li. Mutating E-cadherin in rats to model invasive lobular breast cancer 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 2176.
Lin et al. (Fri,) studied this question.