Microenvironmental Regulation of BRCA1 Gene Expression by c-Jun and Fra2 in Premalignant Human Ovarian Surface

ReducedBRCA1geneexpressioniscommoninthesporadicformofovariancarcinoma.Thespreadofthishighly lethal cancer often begins when tumor cell clusters are shed into the fluid of the abdominopelvic cavity such that theycan floatfreelybeforeseedingdistantsitesontheperitonealwallsandorgans.Thus,themicroenvironmentthat tumor cells find themselves in changes dramatically during these early shedding and floating stages of transperitoneal metastasis. To mimic this microenvironmental change in vitro, we released premalignant human ovarian surfaceepithelialcellsfromthesubstratumandforcedthemtoclusterinsuspension.Undertheseconditions,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 microenvironmental change that is manifested during the initial stages of ovarian carcinoma dissemination may, potentially, helpsuppressBRCA1expressioninsporadictumorsandthuspromotetheirprogression.MolCancerRes;11(3);1– 10. � 2013 AACR.