Abstract 4503: Cycloxygenase-2 and breast cancer prognosis: The role of gene polymorphisms in the regulation of COX-2 expression and their association with histopathological features

Abstract

Introduction: Cycloxygenase-2 (COX-2) overexpression in breast cancer is associated with parameters of aggressiveness, including great tumor size, positive nodal status and lower survival. COX-2 is encoded by a polymorphic gene, PTGS2, with variant alleles in regulatory sites of the promoter and of the 3′-untranslated regions. Aim: To investigate the association between the haplotypes formed by the for most frequent PTGS2 SNPs (rs689465, rs689466, rs20417 and rs5275) and: 1) histopathological parameters with prognostic value on clinical outcome of breast cancer; 2) COX-2 expression in breast tumors. Methods: The study was conducted at the Brazilian National Cancer Institute with 606 women with non-metastatic breast cancer (Protocols #116/07 and #129/08). Recruitment occurred between Jan/ 2008 and Dec/2010 and all patients were genotyped using PCR-RFLP or Real Time-PCR. PTGS2 haplotypes were inferred using the computer software Haploview 4.2, and the individual histopathological profiles were obtained from data available in electronic medical records. The expression of PTGS2 gene in breast tumors was evaluated by the amounts of mRNA transcripts determined with Real Time RT-PCR and by the amounts of COX-2 determined with immunohistochemistry (IHC) in paraffin-embedded tissues. Results: A total of 8 PTGS2 haplotypes were inferred, whose distribution varied as a function of tumor size (P: 0.011), estrogen receptor (ER) status (P: 0.018) and HER2 status (P: 0.025). PTGS2 haplotype *7 (formed by rs689465G, rs689466A, rs20417C, rs5275T) was positively associated with higher tumor size (OR: 3.72, 95%CI: 1.19-11.22, P: 0.006), ER negativity (OR: 2.43, 95%CI: 0.97-5.98, P: 0.032), progesterone receptor (PR) negativity (OR: 2.58, 95%CI: 1.05-6.39, P: 0.02), and HER2 positivity (OR: 4.17, 95%CI:1.19-14.44, P: 0.007). The results also indicated positive associations between variant genotypes of rs689465 and ER negativity (OR: 1.59, 95%CI: 1.04-2.44, P: 0.02) or HER2 positivity (OR: 1.79, 95%CI: 1.00-3.18, P: 0.03), and between variant genotypes of rs20417 and ER negativity (OR: 1.75, 95%CI: 1.15-2.57, P:0. 005), PR negativity (OR: 1.56, 95%CI: 1.09-2.22, P: 0.01) or HER2 positivity (OR: 1.80, 95%CI: 1.04-3.13, P: 0.02). In contrast, variant genotypes of rs689466 were negatively associated with ER negativity (OR: 0.57, 95%CI: 0.33-0.98, P: 0.03). The analyses of PTGS2 expression in breast tumors are currently under course, with 166 tumor species submitted to IHC and 100 submitted to Real Time RT-PCR. Conclusion: Our results suggest that PTGS2 haplotype *7 may contribute to higher growth of untreated breast cancer. We expect that the results regarding the regulation of PTGS2 expression may help understanding the prognostic value of PTGS2 SNPs in breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4503. doi:1538-7445.AM2012-4503