Poly(ADP-ribose) polymerase inhibition: a new direction for BRCA and triple-negative breast cancer?

Inhibitors of poly(ADP-ribose) polymerase (PARP)-mediated DNA repair have shown promise in early clinical studies in the treatment of specific subgroups of breast cancer. Notably, phase II trials indicate that olaparib, an oral PARP inhibitor, has activity as a single agent in BRCA-related tumours, and that a combination of iniparib, an intravenous PARP inhibitor, and chemotherapy offers a survival advantage, compared with chemotherapy alone, in triple-negative breast cancer. Phase III data on the latter indication are expected in 2011. Intriguingly, iniparib does not increase toxicity when used as a chemo-potentiating agent, suggesting that it differs in its mechanism of action from other agents in this class. Overall, PARP inhibitors represent a potentially important new class of anti-cancer agents with two potential modes of action, as single agents causing synthetic lethality and as chemo-potentiating agents

Enhancing enhancers: new complexities in the retinoid regulation of gene expression

Retinoic acid is a signalling molecule central to morphogenesis and musculoskeletal development. It can exist in several isomeric forms, of which all-trans- and 9-cis-retinoic acid are thought to be the most relevant as signalling molecules. Retinoic acid regulates gene expression via RARs (retinoic acid receptors) working as heterodimers with RXRs (retinoid X receptors). RXRs also heterodimerize with other nuclear receptors. In this issue of the Biochemical Journal, Harris et al. have shown that an enhancer responsible for chondrocyte-specific expression of the col11a2 gene is itself regulated by a retinoic-acid-dependent interaction with RXRβ bound to a downstream response element. Thus, RXRs bound to hormone-response elements can regulate gene expression indirectly via interactions with tissue-specific enhancers. This study raises interesting questions about the nature of the response element, the RXRβ partner and the ligands able to influence col11a2 expression, and will provide a model system with which to understand tissue and ligand specificity of retinoid responses