BioProject

Primary skin fibroblasts from HGPS patients and an age-matched control wild-type individuals were challenged in a standard transformation assay by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S). More...

Primary skin fibroblasts from HGPS patients and an age-matched control wild-type individuals were challenged in a standard transformation assay by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S). TERT-Immortalized cell lines from the same sources were also generated. Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis. Overall design: 2 independent cell lines are included for each of the 4 groups (TERT-WT, TRS-WT, TERT-HGPS and TRS-HGPS) Less...