Rat somatic genome editing enables ER+ breast cancer modeling

Genetically engineered mouse models have advanced cancer research but often fail to capture key features of certain human tumors. Rats, with distinct physiology and tumor biology, offer a powerful alternative, yet their use has been constrained by technical barriers to genome editing. Here, we develop efficient somatic genome editing approaches in rats, enabling both indel and substitution mutations, and apply them to model estrogen receptor (ER)-positive breast cancer, which represents ~70% of human cases but remains poorly represented in mice. The resulting rat tumors closely recapitulate human disease in histology, hormone responsiveness, and microenvironmental features. By contrast, identical genetic alterations in mice failed to yield ER+ tumors, underscoring fundamental species differences in tumorigenesis. This platform provides a versatile and scalable platform for rapid generation of clinically relevant rat tumor models, opening new avenues to investigate mechanisms of tumor biology, therapeutic response, and immune interactions in previously inaccessible cancer subtypes.