miR-1297 is frequently downmodulated in flat epithelial atypia of the breast and promotes mammary neoplastic transformation via EphrinA2 regulation

: Breast cancer ranks as the most prevalent form of cancer globally. Currently, advanced screening methods have significantly improved early detection rates. These achievements have led to more non-invasive cancer diagnoses and underscored the clinical relevance of precursor lesions like flat epithelial atypia (FEA), a histological condition characterized by mild atypical changes in the normal epithelium lining the mammary ducts. Despite the increasing detection of FEA in mammary biopsy, our understanding of the biological behavior of this entity remains limited and, as a consequence, the clinical management of patients is still being debated. Evidence from the literature indicates that dysregulation of microRNAs contributes to all stages of breast cancer progression, potentially serving as valuable markers of disease evolution. In this study, through a comparison of the microRNA profiles of normal mammary epithelium, FEA, and non-invasive breast cancer in three cohorts of patients, we identified downregulation of miR-1297 as a common feature in both FEA and non-invasive breast cancer compared to the normal counterpart. Mechanistically, overexpression of miR-1297 inhibits the growth of breast cancer cells by targeting the oncogenic receptor tyrosine kinase EphrinA2. In contrast, downregulation of miR-1297 increases proliferation and alters the morphology of normal mammary epithelial cells in a three-dimensional context. These findings pinpoint the downregulation of miR-1297 as an early event in mammary transformation and suggest its potential role as a driver of progression in FEA, harboring the capacity to evolve into malignancy.