HER2∆16 directs luminal cell identity and estrogen receptor signaling in HER2+ breast cancer

Co-expression of the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) contributes to breast cancer heterogeneity and therapeutic resistance. However, the molecular mechanisms promoting ER positivity within HER2+ cancers remains largely unknown. Here we show, across HER2+ transgenic mouse models the oncogenic HER2 splice variant lacking exon 16 (HER2∆16) promotes the development of aggressive luminal tumors by facilitating an ER-mediated transcriptional program which is sensitive to endocrine therapies. HER2∆16 is detected across human HER2+ breast tumors and cell lines with higher levels correlating with increased expression of ER and downstream transcriptional targets. Notably, in human cell lines HER2∆16 expression is elevated upon acquired resistance to HER2-targeted therapy and can sensitize cells to the ER-antagonist tamoxifen. Overall, these findings offer valuable insights into the role of HER2∆16 in promoting luminal cell identity and estrogen receptor positivity in breast cancer, providing a useful platform to model HER2+/ER+ disease.