DNA Damage and Repair Microenvironmental Regulation of BRCA1 Gene Expression by c-Jun and Fra2 in

ReducedBRCA1 gene expression is common in the sporadic form of ovarian carcinoma. The spread of this highly lethal cancer often begins when tumor cell clusters are shed into the fluid of the abdominopelvic cavity such that they can float freely before seeding distant sites on the peritoneal walls and organs. Thus, themicroenvironment that tumor cells find themselves in changes dramatically during these early shedding and floating stages of transper-itoneal metastasis. To mimic this microenvironmental change in vitro, we released premalignant human ovarian surface epithelial cells from the substratum and forced them to cluster in suspension. Under these conditions, steady state levels of BRCA1 mRNA and protein fell significantly and the transcriptional activation state of the BRCA1 promoter was suppressed. Analysis of the promoter indicated that the previously identified "CRE " element located within the "positive regulatory region " (PRR) contributed to this suppression. More specifically, we show that the suppression was mediated, at least in part, by a suspension culture–driven decrease in the levels of two members of the AP1 transcription factor complex, c-Jun and Fra2, that bind to the CRE element. Therefore, a microenvi-ronmental change that is manifested during the initial stages of ovarian carcinoma dissemination may, potentially, help suppress BRCA1 expression in sporadic tumors and thus promote their progression. Mol Cancer Res; 11(3); 272–81. 2013 AACR