Androgens play an important role in the development and the maintenance of the normal prostate gland. Androgen Receptor (AR) signaling is also critical during the initiation and development of prostate cancer that may present with a range of genomic lesions possibly due to DNA repair defects. We first noted a significant correspondence between DNA breakpoints and AR binding sites supporting the inter-related action that hormone regulation plays a role on genomic events. We hypothesized that heritable variants, i.e. individuals genetics, encode predisposition to genomic instability in the context of AR signaling that undergoes changes during men lifetime resulting in early recurrent prostate cancer specific somatic genomic events. Using a mathematical score and interrogating the transcriptome of human prostate tissue cells we identified a polymorphic regulatory element that associates with DNA repair and hormone regulated gene transcripts and with early recurrent prostate cancer specific somatic mutations. The locus showed allele-specific regulatory activity that is concomitantly modulated by the Androgen Receptor (AR) and the CCAAT/Enhancer Binding Protein (C/EBP) beta (CEBPB), altogether suggesting that the locus is involved in a hormone dependent DNA damage response.
Biographical details: Francesca Demichelis is Associate Professor of Molecular Biology at the University of Trento, Italy. She is expert in the area of Cancer Genomics. Her laboratory focuses on the characterization of tumor evolution and progression through the study of intra- and inter-tumor heterogeneity using single base level information from tissue biopsies or circulating DNA (cell-free DNA). She has longstanding interest in the impact of inherited polymorphisms within transcriptionally active regulatory regions on the initiation of hormone regulated cancer phenotypes.