TITLE: 'REGULATORY MECHANISMS IN TUMORIGENESIS'. SUBTITLE: 'THE DOWNREGULATION OF HOXA2 GENE IN BREAST CANCERS'.

Breast cancer (BC) is a heterogeneous group of diseases, each one characterized by different biological, molecular and clinical features. Accumulating evidences indicated the currently promising role of genetic and epigenetic subtype-specific biomarkers for BC early detection and disease monitoring. HOXA2, a member of the HOX gene family, is a transcription factor involved in gene expression regulation during embryonic development. Dysregulation of HOXA2 expression has been associated with different cancers. However, limited information is available on HOXA2 expression and functions in breast tumorigenesis. Here, we have demonstrated that HOXA2 is significantly downregulated in human BC tissues and cell lines. Immunohistochemistry and survival curve analysis showed a significant negative correlation between the downexpression of HOXA2 and histological grading, tumor stage and lymph node involvement, and relapse-free survival in hormone positive BC patients, respectively. At functional level, we demonstrated that HOXA2-knockdown significantly enhances cell proliferation, cell migration and invasion. In contrast, HOXA2 increased expression induced by HOXA2-overespression remarkably inhibits cell proliferation. In conclusion, our data provide evidence that HOXA2 is a tumor suppressor gene, whose downregulation is implicated in BC progression and predicts poor relapse-free survival rate in BC patients.