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Poster display session

3601 - Kynurenine-3-monooxygenase (KMO) protein promotes triple negative breast cancer progression

Date

11 Sep 2017

Session

Poster display session

Presenters

Chun-Yu Liu

Citation

Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361

Authors

C. Liu1, T. Huang1, C. Lee1, W. Wang1, H. Lee2, L. Tseng3

Author affiliations

  • 1 Oncology, Taipei Veterans General Hospital, 11217 - Taipei/TW
  • 2 Department And Institute Of Pharmacology, National Yang-Ming University, 11217 - Taipei/TW
  • 3 Surgery, Taipei Veterans General Hospital, 112 - Taipei/TW
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Abstract 3601

Background

Triple-negative breast cancer (TNBC) remains a difficult-to-treat cancer and the biology beneath TNBC is a research interest. Tryptophan-kynurenine metabolism plays an important role in epithelial-mesenchymal transition (EMT), cancer stem cells (CSCs) and immune escape. Previous studies have focused on the expression and function of the first step and the rate-limiting enzyme in tumor cells, whereas the second step catabolic enzyme kynurenine 3-monooxygenase (KMO) was rarely addressed in tumorigenesis. Hence, we sought to investigate of the mechanism and functions of KMO in TNBC carcinogenesis.

Methods

KMO gene alteration and mRNA transcripts were analyzed from the The Cancer Genome Atlas (TCGA) database. MDA-MB-231 and MDA-MB-468 TNBC cell lines were used for in vitro studies. Cell proliferation, colony formation, transwell migration/invasion assays and tumorsphere forming ability were used for functional study. Signal transduction pathways were assessed by Western blot, quantitative real-time PCR and reporter assays. The effect of KMO on tumor growth was tested in nude mice with breast cancer xenografts.

Results

TCGA analysis showed high-frequency of KMO amplification alterations, which was related to poor overall survival in breast cancers. KMO transcripts were up-regulated in the tumor tissues of breast cancers, especially in TNBC. The functional assays showed that ectopic KMO expression promoted tumorigenesis, including cell growth and abilities of colony formation, migration, invasion, and tumorsphere formation. Moreover, western blot analysis revealed expressions of epithelial marker E-cadherin were decreased and mesenchymal markers N-cadherin, and Twist were increased by KMO overexpression in MDA-MB-468 cells. Interestingly, the mRNA and protein levels of pluripotency genes including CD44, Nanog, Oct4, and SOX-2 were also suppressed by KMO knockdown. Data of reporter gene assay showed that the activities of Nanog, Oct4, and SOX-2 promoters were enhanced by KMO overexpression. Furthermore, knockdown KMO decreased the xenografted tumor growth of MDA-MB-468 cells, suggesting its oncogenic role in TNBC.

Conclusions

Our data highlight the novel and critical roles of KMO in TNBC progression and metastasis.

Clinical trial identification

Not applicable

Legal entity responsible for the study

Taipei Veterans General Hospital

Funding

Taipei Veterans General Hospital

Disclosure

All authors have declared no conflicts of interest.

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