HER2Δ16 directs luminal cell identity andestrogen receptor signaling in HER2+breast cancer

Abstract
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 (HER2Δ16) promotes the development of aggressive luminal tumors by facilitating an ER-mediated transcriptional program which is sensitive to endocrine therapies. HER2Δ16 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 HER2Δ16 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 HER2Δ16 in promoting luminal cell identity and estrogen receptor positivity in breast cancer, providing a useful platform to model HER2+/ER+ disease.