title: Cancer/stroma interplay via cyclooxygenase-2 and indoleamine 2,3-dioxygenase promotes breast cancer progression.
abstract: BACKGROUND
  Expression 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.
  
  
  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) 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.
  
  
  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 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.
  
  
  CONCLUSIONS
  Integration 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.
authors: Jing-Yi
authors: JY
authors: Chen
authors: Chien-Feng
authors: CF
authors: Li
authors: Cheng-Chin
authors: CC
authors: Kuo
authors: Kelvin K
authors: KK
authors: Tsai
authors: Ming-Feng
authors: MF
authors: Hou
authors: Wen-Chun
authors: WC
authors: Hung
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D018920:Coculture Techniques; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007737:Kynurenine / Q000494:pharmacology; D061986:MCF-7 Cells; D055442:Metabolome; D055432:Metabolomics; D051379:Mice; D008875:Middle Aged; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D059748:Proteolysis / Q000187:drug effects; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000378:metabolism; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism*
chemical_list: D015820:Cadherins; D052246:Cyclooxygenase 2 Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D058309:Receptors, Prostaglandin E, EP4 Subtype; D044786:S-Phase Kinase-Associated Proteins; D050796:STAT3 Transcription Factor; D007737:Kynurenine; D051546:Cyclooxygenase 2; D015232:Dinoprostone