Chromatin Remodeling in Response to BRCA2-Crisis

Abstract

Summary: Individuals with a single functional copy of the BRCA2 tumor suppressor have elevated risks for breast, ovarian, and other solid tumor malignancies. The exact mechanisms of carcinogenesis due to BRCA2 haploinsufficiency remain unclear, but one possibility is that at-risk cells are subject to acute periods of decreased BRCA2 availability and function (“BRCA2-crisis”), which may contribute to disease. Here, we establish an in vitro model for BRCA2-crisis that demonstrates chromatin remodeling and activation of an NF-κB survival pathway in response to transient BRCA2 depletion. Mechanistically, we identify BRCA2 chromatin binding, histone acetylation, and associated transcriptional activity as critical determinants of the epigenetic response to BRCA2-crisis. These chromatin alterations are reflected in transcriptional profiles of pre-malignant tissues from BRCA2 carriers and, therefore, may reflect natural steps in human disease. By modeling BRCA2-crisis in vitro, we have derived insights into pre-neoplastic molecular alterations that may enhance the development of preventative therapies. : Gruber et al. identify EGF-independent proliferation in mammary cells following transient BRCA2 depletion (“BRCA2-crisis”). In the absence of recurrent genomic mutations, chromatin remodeling mediated by NF-κB signaling drives gene expression changes. This in vitro model shares molecular commonalities observed in BRCA2+/− carriers. Keywords: BRCA2, breast cancer, carcinogenesis, epigenetics, H4K12Ac, haploinsufficiency, histone acetylation, NF-κB