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Semmlinger, Anna; Schönfeldt, Viktoria von; Wolf, Verena; Meuter, Alexandra; Kolben, Theresa Maria; Kolben, Thomas; Zeder-Goess, Christine; Weis, Florian; Gallwas, Julia; Würstlein, Rachel; Hermelink, Kerstin; Schmoeckel, Elisa; Harbeck, Nadia; Mayr, Doris; Mahner, Sven; Jeschke, Udo; Ditsch, Nina (2018): EP3 (prostaglandin E2 receptor 3) expression is a prognostic factor for progression-free and overall survival in sporadic breast cancer. In: BMC Cancer 18:431
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Background: In various cancers, overexpression of cyclooxygenase (COX)-2 and elevated prostaglandin (PG) E2 synthesis have been associated with tumor development and progression. The potential of COX-2 inhibitors in cancer prevention and treatment has been shown repeatedly;however, their clinical use is limited due to toxicity. PGE2 signals via EP receptors 1-4, whose functions are analyzed in current research in search for targeted anti-PG therapies. EP2 and EP4 rather promote tumorigenesis, while the role of EP3, especially in breast cancer, is not yet clear and both pro-and anti-tumorigenic effects have been described. Our study evaluates EP3 receptor expression in sporadic breast cancer and its association with clinicopathological parameters, progression-free and overall survival. Methods: Two hundred eighty-nine sporadic breast cancer samples without primary distant metastasis were immunohistochemically analyzed for EP3 receptor expression. Tissue was stained with primary anti-EP3-antibodies. Immunoreactivity was quantified by the immunoreactivity-score (IRS);samples with an IRS >= 2 scored as EP3 positive. Chi-squared and Mann-Whitney-U test were used for comparison of data;Kaplan-Meier estimates and Cox-regression were used for survival analyses. Results: EP3 receptor was expressed in 205 of 289 samples analyzed (70.9%). EP3 receptor expression was not associated with clinicopathological parameters (e. g. tumor size, hormone receptors, lymph node status). Kaplan-Meier estimates showed a significant association of EP3 positivity with improved progression-free survival (p = 0.002) and improved overall survival (p = 0.001) after up to 10 years. Cox regression analysis confirmed EP3 positivity as a significant prognostic factor even when other known prognosticators were accounted for. Conclusions: In sporadic breast cancer, EP3 receptor expression is not significantly associated with clinicopathological parameters but is a significant prognostic factor for improved progression-free and overall survival. However, the functional aspects of EP3 receptor in breast cancer and the way how EP3 may oppose the pro-tumorigenic effects of PGE2 elevation and COX-2 overexpression are not fully understood so far. Further studies aiming at identification of the factors regulated by EP3 are necessary to evaluate the possibility of targeting EP3 in future anti-tumor therapy in breast cancer.