HER2d16 promotes breast cancer metastasis through integrin-driven signaling

The HER2d16 splice variant, generated by skipping exon 16 of the ERBB2 transcript, is frequently detected in aggressive HER2-positive breast tumors and has been associated with enhanced tumorigenicity. However, the mechanisms by which HER2d16 promotes metastasis remain poorly understood. Here, we demonstrate that HER2d16 expression in mammary epithelial cells drives a pro-migratory and pro-invasive phenotype both in vitro and in vivo. Through integrative cell surface proteomics and transcriptomic profiling, we identify a distinct upregulation of RGD-binding integrins, including integrin β3, in HER2d16-expressing cells. Functional analyses demonstrate that integrin β3 signaling is required for HER2d16-driven invasion, and that pharmacological inhibition of FAK downstream of integrin engagement significantly reduces metastatic dissemination in vivo. Together, these findings reveal a critical link between HER2d16 expression and integrin-FAK signaling programs that drive metastatic progression, highlighting integrin-FAK signaling as a therapeutically actionable vulnerability in HER2-driven breast cancer.