Abstract 3380: HER2 overexpression induces breast tumorigenesis in a non cell autonomous manner by inducing oxidative stress in the tissue microenvironment

Abstract Breast cancer is the most common cancer type in the world. Approximately 70% of pre-malignant breast tumours, known as ductal carcinoma in situ (DCIS), and 20% of invasive breast tumours overexpress HER2. Although molecular mechanisms of HER2 function in breast tumour cells have been extensively studied, our knowledge on how HER2 drives breast tumourigenesis at its pre-malignant stage is quite limited. Here, we investigate the HER2-overexpression driven cellular events at the earliest stages of breast tumourigenesis using in vitro, in vivo and ex vivo models. Using mouse models of HER2+ breast cancer and clinical samples of patients with DCIS, we showed that breast cancer stem cells (BCSCs) reside in HER2-negative population of tumour cells and arise from a HER2-negative cell-of-origin. Proteomics and metabolomics analyses of mammary ducts isolated from the MMTV-Neu mice at the pre-cancerous stage showed that HER2/Neu overexpression alters the energy metabolism in mammary epithelial cells in vivo. Furthermore, we have observed an accumulation of reactive oxygen species levels in pre-cancerous mammary ducts, which consequently causes oxidative stress induction and DNA damage in both HER2-positive and HER2-negative epithelial cells. Collectively, our findings indicate that HER2 overexpression in normal mammary epithelia may lead to a genotoxic tissue microenvironment that may consequently result in the accumulation of further somatic mutations in HER2-negative cell populations, which contain BCSCs and their cell-of-origin. Our findings therefore illustrate a novel mechanism explaining the HER2-driven breast tumour initiation and thus provide new avenues of research for developing novel preventive approaches against breast cancer. Citation Format: Sevim Beyza Gurler, Oliver Wagstaff, Lili Dimitrova, Fuhui Chen, Robert Pedley, William Weston, Ian Donaldson, Brian A. Telfer, David Novo, Kyriaki Pavlou, George Taylor, Yaqing Ou, Kaye Williams, Andrew Gilmore, Keith Brennan, Ahmet Ucar. HER2 overexpression induces breast tumorigenesis in a non cell autonomous manner by inducing oxidative stress in the tissue microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3380.