HER2 overexpression initiates breast tumorigenesis non-cell-autonomously by inducing oxidative stress in the tissue microenvironment

HER2 is considered as a driver oncogene responsible for the HER2+ subtype of breast cancer. However, it is still unclear how HER2 induces the oncogenic transformation of breast cancer stem cells (BCSCs) and initiates tumorigenesis during premalignant stage breast cancer. Here, we used clinical samples and mouse models of HER2+ breast cancer to demonstrate that neither BCSCs nor their cell-of-origin express HER2/Neu in early-stage breast tumors. Instead, our results demonstrate that Neu overexpression results in the transformation of BCSCs in a non-cell-autonomous manner via triggering DNA damage and somatic mutagenesis in their Neu-negative cell-of-origin. This is caused by the increased oxidative stress in the tissue microenvironment generated by altered energy metabolism and increased reactive oxygen species levels in Neu-overexpressing mammary ducts. Therefore, our findings illustrate a previously unrecognized mechanism of HER2-induced breast tumor initiation in vivo with potential impacts on future preventive treatments for HER2+ premalignant breast cancer.