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HER2∆16 directs luminal cell identity and estrogen 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. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE301629 | GEO | 2026/05/16

REPOSITORIES: GEO

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Project description:Circulating tumour cells in women with advanced oestrogen-receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer acquire a HER2-positive subpopulation after multiple courses of therapy. In contrast to HER2-amplified primary breast cancer, which is highly sensitive to HER2-targeted therapy, the clinical significance of acquired HER2 heterogeneity during the evolution of metastatic breast cancer is unknown. Here we analyse circulating tumour cells from 19 women with ER+/HER2- primary tumours, 84% of whom had acquired circulating tumour cells expressing HER2. Cultured circulating tumour cells maintain discrete HER2+ and HER2- subpopulations: HER2+ circulating tumour cells are more proliferative but not addicted to HER2, consistent with activation of multiple signalling pathways; HER2- circulating tumour cells show activation of Notch and DNA damage pathways, exhibiting resistance to cytotoxic chemotherapy, but sensitivity to Notch inhibition. HER2+ and HER2- circulating tumour cells interconvert spontaneously, with cells of one phenotype producing daughters of the opposite within four cell doublings. Although HER2+ and HER2- circulating tumour cells have comparable tumour initiating potential, differential proliferation favours the HER2+ state, while oxidative stress or cytotoxic chemotherapy enhances transition to the HER2- phenotype. Simultaneous treatment with paclitaxel and Notch inhibitors achieves sustained suppression of tumorigenesis in orthotopic circulating tumour cell-derived tumour models. Together, these results point to distinct yet interconverting phenotypes within patient-derived circulating tumour cells, contributing to progression of breast cancer and acquisition of drug resistance. Seventy-four single candidate CTCs from two representative ER+/HER2- patients (BRx-42 and BRx-82) and 14 triple negative patients were isolated via micromanipulation and subjected to single-cell RNA-sequencing. Thirteen candidate CTCs expressed PTPRC at a level higher than 10 reads-per-million, so were deemed potential White Blood Cells and therefore dropped from further consideration. Expression profiles of CTCs expressing ERBB2 at a level greater than 10 RPM were compared with those expressing ERBB2 at a level less than 10 RPM.

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

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