The autoimmune regulator gene (AIRE) plays a fundamental role in tolerance by promoting the expression of tissue-specific antigens in medullary thymic epithelial cells (mTECs). Recently, AIRE expression was detected also in human keratinocytes and in tumors originating in stratified epithelia. Here, we tested whether AIRE is expressed in cancer cells. We analyzed AIRE expression in cancer cases from The Cancer Genome Atlas (TCGA) RNA-seq dataset and we found association with better outcome. AIRE protein expression was verified by immunohistochemistry in a cohort of 39 human breast cancer specimens and its prognostic relevance was confirmed in microarray-based gene expression data set NKI-295 and KM-Plotter. Both in the RNA-seq and gene expression datasets analyzed, AIRE expression was an independent strong prognostic factor for relapse-free survival (RFS), particularly in estrogen receptor-positive tumors. Enrichment of translation-related pathways was observed in AIRE-expressing tumors by Ingenuity Pathway Analysis and a significant increase of cells in G1 phase and activation of caspase cascades was induced by AIRE transfection in breast cancer luminal cell lines, suggesting that AIRE-induced over-translation of proteins lead to cycle arrest and apoptosis. These data are the first to identify AIRE expression in breast cancer and an association with prognosis.