Abstract
Introduction: The most common histotype representing 90% of ovarian cancer cases is High Grade Serous Carcinoma. In a previous publication we found C/EBP-δ to be significantly increased in fallopian tube epithelial in BRCA1 mutation carriers and specifically in the luteal phase of the menstrual cycle, by transcription and protein expression. C/EBP-δ represents a master regulator of gene transcription primarily through STAT3 activation in many tumor types. C/EBP-δ is commonly induced by stress and is associated with increased DNA damage. Additionally, studies in breast cancer showed that C/EBP-δ could interact with FANCD2, which is involved in DNA repair along with BRCA1 and BRCA2. C/EBP-δ plays a dichotomous role in tumor suppression and promotion, which is tissue specific. We therefore studied the 1) differential expression of C/EBP-δ in serous carcinoma 2) expression of C/EBP-δ in precursor lesions (STIC) and 3) modeled the effect of over-expression of C/EBP-δ in an in vitro fallopian tube cell culture model.
Methods: The study protocol for collection of tissue and clinical information for all patients was approved by the UHN REB. Tissue microarrays containing the different histotypes were used to validate immunohistochemical protein expression. Fallopian tubes with lesions classified as STIC using published diagnostic criteria, were selected (n=15) from women undergoing surgery for HGSC. FTE Cells were propagated on collagen IV coated plates in MCDB105/M199 media supplemented with BPE, EGF, insulin and hydrocortisone. Cells were immortalized via double infection with a lentiviral dominant negative TP53 vector and retroviruses with E7 and hTERT. Statistical analysis was performed using ANOVA (p<0.05) and Fisher’s Exact Test p<0.05).
Results/Conclusion: C/EBP-δ is down-regulated in over 60% of HGSC analyzed, an observation which is also histotype specific as LGSC tumors show high expression levels (p<0.01). 60% of C/EBP-δ protein expression exhibited a gradual decrease from the normal FTE to the p53-signatures and the STICs and lost in concomitant HGSC. This indicates an inverse correlation between C/EBP-δ and proliferative index. This suggests that C/EBP-δ regulates cell-cycle progression in the FTE possibly through the G2/M checkpoint and is a potential tumor suppressor in HGSC. In short-term cultures of FTE cell lines, over-expression of C/EBP-δ did not affect proliferation but may affect long-term growth. High expression of C/EBP-δ in FTE cells correlated with decreased vimentin, N-cadherin, ACTA2 and Zeb2 while and in Twist1 and mir21 expression. This data is consistent with the phenotypic effect observed by over-expressing C/EBP-δ in cell culture and indicates an involvement of C/EBP-δ in mesenchymal-to-epithelial transition during high-grade serous carcinogenesis.
Citation Format: Sophia HL George, Ramlogan Sowamber, Patricia Shaw. The role of BRCA and CEBPD in serous ovarian cancer carcinogenesis [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1312.
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