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

Abstract

Reduced BRCA1 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, the microenvironment that 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 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 microenvironmental 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. Ó2013 AACR. IntroductionEpithelial ovarian carcinoma is the leading cause of death due to gynecologic malignancy (1). The great majority of these deaths occur in women who present with high-grade serous subtype tumors that metastasize by spreading transperitoneally through the abdominopelvic cavity. High-grade serous subtype tumors are also notable because they also have the highest rate of BRCA1 abnormalities, a considerable proportion of which occur due to epigenetic silencing rather than mutation (2). Given BRCA1 0 s myriad roles in acting to maintain genomic stability and differentiation, determining

FAM49B, a novel regulator of mitochondrial function and integrity that suppresses tumor metastasis

“…The tumor microenvironment is known to affect the regulation of genes, and the expression other tumor suppressor genes, such as BRAC1 and PTEN , is downregulated in the tumor environment. 41 , 42 Here, we showed that FAM49B plays a suppressive role in PDAC, as shFAM49B PDAC cells displayed higher proliferation and invasive ability than their counterparts, both in vitro and in vivo , confirming our initial hypothesis.…”

Selective participation of c-Jun with Fra-2/c-Fos promotes aggressive tumor phenotypes and poor prognosis in tongue cancer

“…It gains support from recent report of Mariani et al (2007) who demonstrated amplification and overexpression of c-Jun can block adipocytic differentiation leading to undifferentiated highly aggressive tumors 40 . Zhou et al (2013) also showed that changes in BRCA1 gene expression is regulated by c-Jun and Fra-2 that bind to the CRE element in early stages of ovarian carcinoma that suppress BRCA1 expression in sporadic tumors and promote tumor progression 41 . Together, these findings suggest that selective participation of c-Jun with c-Fos-Fra-2 protein complex of AP-1 plays an important role in maintaining undifferentiated tumor phenotype, aggressiveness and poor prognosis that may lead to drug resistance, treatment failure and disease relapse.…”

FOSL2 Positively Regulates TGF-β1 Signalling in Non-Small Cell Lung Cancer

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