NCI scientists have studied cells of patients with an extremely rare genetic disease that is characterized by drastic premature aging and discovered a new protective cellular mechanism against cancer. They found that cells from patients with Hutchinson Gilford Progeria Syndrome (HGPS), who typically do not develop cancer, contain a tumor protection mechanism that is mediated by BRD4 (Bromodomain-containing protein 4, a protein that is encoded by the BRD4 gene). Importantly, the NCI scientists found that this tumor protection mechanism has relevance to more than just HGPS patients. Although the tumor protective role of BRD4 was greatly enhanced in HGPS patient cells, the same pathway also appears to be at work in the general population, as shown by analyses of clinical outcome data in several patient groups, including those with breast and lung cancers. The study, headed by Tom Misteli, Ph.D., head of the Cell Biology of Genomes Group in NCI’s Laboratory of Receptor Biology and Gene Expression, and colleagues, appeared online October 2, 2014, in Cell Reports.
The goal of this study was to uncover the mechanism for HGPS patients’ remarkable resistance to cancer. First, the scientists confirmed that HGPS cells have intrinsic mechanisms that prevent them from producing tumors. They then used molecular technologies to identify proteins that mediate this resistance against cancer and with this approach they identified BRD4. The scientists next investigated whether BRD4 plays a more general tumor-protective role in the general population. Previous findings had suggested that BRD4 expression limits metastasis in breast cancer and lung cancer, and by examining clinical samples of these cancers, the researchers found that expression of BRD4-sensitive genes was associated with better patient survival in breast and lung cancer patients. In contrast, the BRD4-sensitive gene signature was associated with poor outcomes in patients with hematologic cancers, such as leukemia, which previous findings had suggested may be promoted by BRD4. It thus seems that BRD4 has different effects in different tissues and can act both as a tumor promoter and a tumor protector, depending on the tissue. Next steps will be studies to fully understand and therapeutically exploit BRD4’s tumor protective role.