Abstract
Abstract Purpose: Tryptophan-kynurenine pathway involves in inflammation, immune response and tumorigenesis, in which kynurenine 3-monooxygenase (KMO), an outer mitochondrial membrane protein, mediating kynurenine metabolism. Previous studies indicated KMO showed increased activity in breast cancer. Triple-negative breast cancer (TNBC) tumors exhibited elevated levels of tryptophan metabolites compared to estrogen receptor positive breast cancers. We aimed to study the role of KMO in human TNBC. Experimental design: The gene alterations and transcripts of enzymes in kynurenine metabolism were analyzed from The Cancer Genome Atlas (TCGA) database. Immunohistochemical staining for KMO was performed and a H-score was assigned to quantify protein expression. Epithelial-mesenchymal transition (EMT) phenotypes were examined by transwell assay and EMT markers expressions. Stemness properties were assessed by mammosphere assay and pluripotent genes expressions. The molecular events were analyzed by Western blot, quantitative real-time PCR and luciferase reporter assay. Tumor growth and metastasis were conducted in nude mice and NOD-SCID mice by subcutaneous and tail vein injection respectively. Results: TCGA databases showed KMO but not KYNU and KAT2 was amplified in breast cancer. Both the data from TCGA and our in-house IHC-based tissue-microarray exhibited increased KMO expression in TNBC compared to normal tissue. In vitro, overexpression of KMO in TNBC cells resulted in increased cell growth and colony formation. The abilities migration and invasion as well as EMT markers expressions of TNBC cells were elevated by KMO overexpression. In addition, KMO increased mammosphere formation, pluripotent genes expressions and promoter activities. However, inhibition of KMO enzymatic activity by KMO inhibitors did not affect cancer progression or mitochondrial respiration of TNBC cells. KMO upregulated β-catenin, the upstream regulator of pluripotent genes, CD44 and Nanog expressions. Mechanistically, data showed KMO expressed in both cytosol and nuclear fractions and was associated with β-catenin. KMO enhanced pluripotent genes expressions through β-catenin upregulation. Importantly, KMO knockdown suppressed tumor growth and expressions of β-catenin, CD44 and Nanog in TNBC tumors. Moreover, KMO knockout significantly decreased lung metastasis in vivo. Conclusion: Our data indicated KMO can play an oncogenic role in TNBC, acting as a novel regulator of pluripotent genes via β-catenin and promoted TNBC progression. Citation Format: Chun-Yu Liu, Tzu-Ting Huang, Ji-Lin Chen, Chia-Han Lee, Wan-Lun Wang, Ka-Yi Lau, Chun-Teng Huang, Pei-Yi Chu, Hsin-Chen Lee, Ling-Ming Tseng. Kynurenine 3-monooxygenase (KMO) acts as a novel oncoprotein in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1711.
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