Abstract
Abstract The high-grade serous ovarian carcinoma (HGSOC), the most aggressive ovarian cancer subtype, constitutes 90% of serous carcinomas and it accounts for two-thirds of ovarian cancer deaths. It is a poorly understood disease with high therapeutic resistance and extremely poor prognosis. The current study is an attempt to analyze molecular mechanisms underlying HGSOC and to identify new therapeutic targets. The Cancer Genome Atlas (TCGA) analyses of ovarian carcinoma demonstrated that p53 mutations are near universal (90%) in HGSOC and forkhead box M1 protein (FOXM1) network is significantly altered in 87% of HGSOC leading to transcriptional upregulation of proliferation-related target genes. Moreover, Mutant p53 and FOXM1 have important roles in resistance to chemotherapy. In the present study, we have used various experimental procedures such as RNAi technology, quantitative real-time PCR, immunoblot analysis, proximity ligation assay (PLA) (to determine protein-protein interaction in situ) and assays for cell cycle, apoptosis and proliferation to analyze signaling crosstalk in OVCAR3 (HGSOC) cells. Our experiments have identified estrogen receptor-beta (ER-beta) as a novel member of the mutant p53-FOXM1 axis. We show that not only mut-p53 and ER-beta physically interact, but also they mutually regulate each other's expression at the gene transcriptional level leading to changes in expression of downstream signaling targets such as FOXM1. Importantly, the effect of knocking down ER-beta on transcription of FOXM1 was similar to that of knocking down endogenous mut-p53, suggesting that both mutant p53 and ER-beta are transcriptional activators of FOXM1. Knocking down ER-beta results in decreased mut-p53 transcript levels suggesting transcription of mut-p53 is activated by ER-beta in OVCAR cells. On the other hand, mut-p53 represses transcription of ER-beta gene. Thus, our experiments have revealed a feedback loop between mut-p53 and ER–beta at the transcriptional level.. We show that when ER-beta was knocked down, FOXM1 levels were decreased and apoptosis was increased. Of note, knocking down ER-beta decreased resistance to cisplatin and carboplatin, major therapeutic agents currently in use for ovarian cancer. Our data provides new insight into the mechanisms underlying HGSOC by illustrating how signaling crosstalk between ER-beta and mut-p53 leads to increased expression of pro-proliferative and pro-tumorigenic downstream targets such as FOXM1, overexpression of which has been associated with resistance to therapeutic agents.in HGSOC patients. Our study will be the first, to the best of our knowledge, to investigate whether the crosstalk between ER-beta and mut-p53 play an important role in the onset and progression of HGSOC. Thus, we have identified mutant p53-ER beta signaling axis as a novel therapeutic target in HGSOC. Citation Format: Chetan C. Oturkar, Gokul M. Das. Estrogen receptor-beta and mutant p53 signaling crosstalk as a novel molecular target to overcome therapeutic resistance in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2135.
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