Purpose:
Tumour immune evasion and poor drug response are two major concerns in the field of breast cancer (BC). One key immune system evasion mechanism results from dysregulation of the kynurenine pathway (KP) of tryptophan metabolism. KP dysregulation has been previously reported in BC patients and is known to be associated with an increased risk of cancer reoccurrence and metastasis. In BC patients who had mastectomy, the KP metabolism is back to normal. Our hypothesis is that hormonally induced KP facilitates breast cancer progression towards metastasis. Thus, by quantifying KP activity would then potentially evaluate the breast cancer risk in patients. However, the biochemical events leading to KP dysregulation and its role in BC remains unclear. Hence, this study aims to investigate the molecular mechanisms underlying KP dysregulation and devise a surrogate KP serum biomarker to assess breast cancer risk.
Methods:
We will use an in vitro approach toprofile KP dysregulation (gene, protein and metabolic expression) in major subtypes of breast cancer (luminal, HER2, and basal). To understand the impact of KP overexpressing tumours on the T-cell population in human BC, immunostaining were be carried out on selected fixed human breast tissue (n=80) to examine T-cells and tumour cells KP expression. Additionally, KP metabolites will also be quantified in the serum of BC patients and controls using ultra high performance liquid chromatography and potential correlation to BC stages have been established.
Conclusion:
KP dysregulation has previously been shown to allow tumoural cells to escape destruction from the immune system, but nothing is known about the ability of the KP to influence outcomes in aggressive forms of breast cancer. The proposed study has addressed this gap in our understanding. The use of selective KP inhibitors could lead to new non-invasive therapies for breast cancer.