Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression (Breast Cancer Research)

IntroductionExpression of indoleamine 2, 3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, clinical significance of stromal IDO and the regulation of stromal IDO are unclear. Methods: Metabolomics and enzyme-linked immunosorbent assay (ELISA) were used to study the effect of cyclooxygenase-2 (COX-2)-overexpressing breast cancer cells on IDO expression in co-cultured human breast fibroblasts. Biochemical inhibitors and short hairpin RNA (shRNA) were used to clarify how prostaglandin E2 (PGE2) up-regulates IDO expression. Associations of stromal IDO with clinicopathological parameters were tested in tumor specimens. Orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth. Results: Kynurenine, the metabolite generated by IDO, increases in the supernatant of fibroblasts co-cultured with COX-2-overexpressing breast cancer cells. PGE2 released by cancer cells up-regulates IDO expression in fibroblasts through an EP4/ Signal transducer and activator of transcription 3 (STAT3)-dependent pathway. On the other hand, fibroblast-secreted kynurenine promotes the formation of the E-cadherin/Aryl hydrocarbon receptor (AhR)/S-phase kinase-associated protein 2 (Skp2) complex, resulting in degradation of E-cadherin to increase breast cancer invasiveness. The enhancement of motility of breast cancer cells induced by co-culture with fibroblasts is suppressed by the IDO inhibitor 1-methyl-tryptophan. Pathological analysis demonstrates that up-regulation of stromal IDO is a poor prognosis factor and is associated with of COX-2 overexpression. Co-expression of cancer COX-2 and stromal IDO predicts a worse disease-free and metastasis-free survival. Finally, COX-2 and IDO inhibitors inhibit tumor growth in vivo. Conclusion: Integration of metabolomics, molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2 and IDO promotes tumor progression and predicts poor patient?s survival.