E-Poster Presentation 33rd Lorne Cancer Conference 2021

Differential kynurenine pathway metabolism in highly-metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression (#144)

Benjamin Heng 1 , Ayse A Bilgin 2 , David B Lovejoy 1 , Vanessa X Tan 1 , Heloisa Helena Milioli 3 , Laurence Gluch 4 , Sonia Bustamante 5 , Tharani Sabaretnam 6 , Pablo Moscato 7 , Chai K Lim 1 , Gilles J Guillemin 1
  1. Department of Biomedical Sciences, Macquaire University, North Ryde, NSW, Australia
  2. Department of Mathematics and Statistics, Macquarie University, North Ryde, NSW, Australia
  3. School of Environmental and Life Sciences, University of Newcastle, Newcastle, NSW, Australia
  4. The Strathfield Breast Centre, Sydney, NSW, Australia
  5. Bioanalytical Mass Spectrometry Facility, University of New South Wales, Sydney, NSW, Australia
  6. Macquarie University, Macquarie Park, NSW, Australia
  7. School of Electrical Engineering and Computing, University of Newcastle, Newcastle, NSW, Australia

Background:Immunotherapy has recently been proposed as a promising treatment to stop breast cancer (BrCa) progression and metastasis. However, there has been limited success in the treatment of BrCa with immune checkpoint inhibitors. This implies that BrCa tumors have other mechanism(s) to escape immune surveillance. While the kynurenine pathway (KP) is known to be a key player mediating tumor immune evasion and while there are several studies on the roles of the KP in cancer, little is known about KP involvement in BrCa.

Methods: To understand how KP is regulated in BrCa, we examined the KP profile in BrCa cell lines (n=7) and clinical samples (n = 1,997) that represent major subtypes of BrCa (luminal, HER2, and triple-negative (TN)). We carried out qPCR, western blot/immunohistochemistry and ultra-high pressure liquid chromatography on these samples to quantify KP enzyme gene, protein and activity respectively.

Results: We revealed that the KP is highly dysregulated in the HER2-enriched and TN BrCa subtype. Gene, protein expression and KP metabolomic profiling have shown that the downstream KP enzymes KMO and KYNU are highly upregulated in the HER2-enriched and TN BrCa subtypes, leading to increased production of the potent immunosuppressive metabolites anthranilic acid (AA) and 3-hydroxylanthranilic acid (3HAA).

Conclusions: Our findings suggest that KMO and KYNU inhibitors may represent new promising therapeutic targets for BrCa. We also showed that KP metabolite profiling can be used as an accurate biomarker for BrCa subtyping, as we successfully discriminated TN BrCa from other BrCa subtypes.

  1. Heng, B., A. A. Bilgin, D. B. Lovejoy, V. X. Tan, H. H. Milioli, L. Gluch, S. Bustamante, T. Sabaretnam, P. Moscato, C. K. Lim and G. J. Guillemin (2020). "Differential kynurenine pathway metabolism in highly metastatic aggressive breast cancer subtypes: beyond IDO1-induced immunosuppression." Breast Cancer Res 22(1): 113.