GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE301nnn/GSE301629/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE301629GEOGSEfalseHER2∆16 directs luminal cell identity and estrogen receptor signaling in HER2+ breast cancerCo-expression of the estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) contributes to breast cancer heterogeneity and therapeutic resistance. 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. HER2∆16 is expressed across HER2+ human breast cancer cell lines with higher levels correlating with increased expression of both ER and downstream transcriptional targets. Interestingly, expression of HER2∆16 is increased upon resistance to HER2-targeted therapy, leading to an ER-driven transcriptional program which can be effectively targeted using ER-antagonists. Overall, these findings offer valuable mechanistic insights into the therapeutic efficacy of combining anti-HER2 and endocrine therapy in tumors expressing high levels of the HER2∆16 isoform either in neoadjuvant or adjuvant settings to better treat HER2+ disease.2026/05/16GSE301629GSM9086669GSM9086668GSM9086667GSM9086666GSM9086661GSM9086670GSM9086665GSM9086664GSM9086663GSM908666224247301629Mus musculus