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ABSTRACT
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.
Abbreviations
| AIRE | = | autoimmune regulator gene |
| mTECs | = | medullary thymic epithelial cells |
| TCGA | = | The Cancer Genome Atlas |
| RFS | = | relapse-free survival |
| OS | = | overall survival |
| IPA | = | Ingenuity Pathway Analysis |
| TSAs | = | tissue-specific antigens |
| eTACs | = | extra-thymic AIRE- expressing cells |
| ER | = | estrogen receptor |
| FFPE | = | Formalin-fixed, paraffin-embedded |
| IHC | = | immunohistochemistry |
| hr | = | hours |
Disclosure of potential conflicts of interest
No potential conflicts of interest were disclosed.
Acknowledgments
We thank: Mrs. G. Abolafio and Dr. I. Muradore, staff members of the Flow Cytometry Core Facilities; Dr. M. Pennati for helpful data discussion; Mrs. C. Ghirelli and Mrs. P. Aiello for technical assistance and Dr. C. Vinci and Dr. C. Storti for technical contribution; Mrs. L. Mameli for manuscript preparation (Fondazione IRCCS Istituto Nazionale Tumori).
Funding
This work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) under Grant 15190. Michele Sommariva is supported by a fellowship from the “Fondazione Umberto Veronesi”
ORCID
Francesca Bianchi http://orcid.org/0000-0001-5197-5279
Michele Sommariva http://orcid.org/0000-0002-7622-0996
Lucia Sfondrini http://orcid.org/0000-0003-0350-5402
