HMGA1 PROTEINS REGULATE GENE EXPRESSION IN TRIPLE-NEGATIVE BREAST CANCER CELLS THROUGH THE MODULATION OF THE EPIGENETIC CODE

Triple negative breast cancers (TNBCs) are high-grade invasive ductal carcinoma which lack expression of hormone receptors and which do not benefit from either endocrine or anti-human epidermal growth factor receptor 2 therapies leading to poor outcome. This heterogeneous group of cancers encompass different molecular subtypes reflecting treatment responsiveness. Among others, mesenchymal-like TNBC subtype is characterized by the enrichment of proteins involved in cell motility and Epithelial to Mesenchymal transition (EMT). High Mobility Group A1 (HMGA1) is a family of oncofetal proteins identified as inducers of this phenotypic transition that have been extensively associated to cancer onset and progression. Despite their well-described role in chromatin architecture and gene expression regulation, their potential role in setting histones post-translational dynamics has never been taken into account. In this thesis, we provide evidences of HMGA1 involvement in histone post-translational modifications modulation by sustaining the RAS/RAF/MEK/ERK/RSK2 pathway in mesenchymal-like TNBC cells. In particular, we suggest that HMGA1 proteins make chromatin prone to epigenetic modifiers actions sustaining both H3 serine 10 phosphorylation by RSK2 and H2B lysine 5 acetylation by CBP and modulating the expression of genes involved in tumor progression and EMT. We suggest that aside being considered as drug target, HMGA1 could be used as biomarker predicting responsiveness to epigenetic therapies in triple negative breast cancers.