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

Tumors expressing both ER and HER2 comprise up to 10% of diagnosed breast cancer cases, yet advances in the field have been hindered by the lack of suitable genetically engineered mouse models (GEMMs) to study the interactions between HER2 and ER in an immune-competent setting.

Here, we demonstrate that expression of the oncogenic HER2 splice variant lacking exon 16 (HER2∆16) within the mammary epithelium promotes the development of aggressive luminal tumors, resembling HER2+/ER+ human breast cancer. Expression of HER2∆16 facilitates luminal cell differentiation and drives an ER-mediated transcriptional program that is sensitive to endocrine-based therapies in both murine and human models. Using a knock-in GEMM where HER2∆16 is under the transcriptional control of the endogenous murine ErbB2 promoter we show that this model recapitulates many features of HER2+/ER+ human breast cancer including genomic amplification of the endogenous ErbB2 allele, ER-expression and sensitivity to anti-estrogens, providing a vital preclinical platform to model ER+/HER2+ disease.