Abstract
IntroductionExpression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. However, the clinical significance of stromal IDO and the regulation of stromal IDO are unclear.MethodsMetabolomics 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) upregulates IDO expression. Associations of stromal IDO with clinicopathologic parameters were tested in tumor specimens. An orthotopic animal model was used to examine the effect of COX-2 and IDO inhibitors on tumor growth.ResultsKynurenine, 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 upregulates IDO expression in fibroblasts through an EP4/signal transducer and activator of transcription 3 (STAT3)-dependent pathway. Conversely, 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 upregulation 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.ConclusionIntegration of metabolomics and molecular and pathological approaches reveals the interplay between cancer and stroma via COX-2, and IDO promotes tumor progression and predicts poor patient survival.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-014-0410-1) contains supplementary material, which is available to authorized users.
Highlights
Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis
ultraperformance liquid chromatography (UPLC)/MS/MS analysis demonstrated that fragmentation of kynurenine standard yielded three peaks with m/z ratio of 209, 192, and 146, which is consistent with the reported data (Figure 1B)
prostaglandin E2 (PGE2) transcriptionally elevated IDO expression in RMF-EG fibroblasts through the prostaglandin E receptor 4 (EP4)/signal transducer and activator of transcription 3 (STAT3) signaling pathway We found that PGE2 increased IDO mRNA and protein levels in RMF-EG cells (Figure 2Ai and 2Aii)
Summary
Expression of indoleamine 2,3-dioxygenase (IDO) in primary breast cancer increases tumor growth and metastasis. Studies of human breast tumor tissues demonstrate that upregulation of COX-2 has been detected in Results of animal study support an oncogenic role of COX-2. Transgenic COX-2 overexpression induces mammary tumor formation in mice [9]. This tumorigenic transformation is highly dependent on PGE2 production and angiogenic switch. HER-2/Neu oncogene-induced mammary tumorigenesis and angiogenesis are dramatically attenuated in COX-2 knockout mice, suggesting a key role of COX-2 in breast cancer [10]. All of the results suggest that COX-2 is involved in multiple steps of breast carcinogenesis and is a potential target for cancer prevention and therapy
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