Nature Communications, Published online: 15 June 2026; doi:10.1038/s41467-026-74435-9 Breast cancers with HER2 overexpression can vary in whether they also express the estrogen receptor, influencing tumor behavior and treatment response. Here, the authors show that in transgenic mouse models, the HER2Δ16 splice variant promotes the development of aggressive luminal tumors by facilitating luminal cell differentiation and driving estrogen receptor signaling that is sensitive to endocrine therapy.