Investigation of the role of the histone modifying enzyme peptidyl arginine deiminase 4 (PAD4) in breast cancer progression

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Breast cancer is the most common tumor in women worldwide and disease progression still remains poorly understood. Recent studies have shown that in addition to genetic mutations, epigenetic alterations also contribute to tumorigenesis, not only at the levels of DNA methylation but also at the level of histone marks and histone modifying enzymes. The aim of this research proposal is to elucidate the role of epigenetic alteration in breast cancer, in particular the role of PAD4, an enzyme that converts histone arginine and methylarginine residues to citrulline. My preliminary data strongly suggest that PAD4 inhibits epithelial-to-mesenchymal-transition in breast cancer cells, a transition event that gives rise to invasive, tumorigenic cancer cells. My proposed studies seek to determine downstream gene targets and underlying pathways of PAD4 by performing microarray and ChIP-sequencing analyses to elucidate how this enzyme is involved preserving an epithelial cell phenotype. Moreover, I will test the hypothesis that downregulation of PAD4 and the resulting reduction of histone citrullination is part of an epithelial-tomesenchymal- transition program in invasive breast cancer cells and can be reversed by the overexpression of PAD4. The expected results of the proposed project will give rise to a better understanding of the role of histone modifications mediated by enzyme PAD4 in breast cancer and will likely be helpful for the development of novel diagnostic and therapeutic strategies in the prevention of breast cancer progression.