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Junior Research Group at IZKF unravels a new role of pyrimidine degradation in maintaining the aggressive nature of triple negative breast cancer

The IZKF Junior Group-1 led by Dr. Paolo Ceppi at the Faculty of Medicine in Friedrich Alexander University of Erlangen-Nuremberg has identified a novel mechanism involving cellular metabolism that is essential for maintenance of triple negative subtypes of breast cancer (which is the most aggressive breast cancer type with a very few treatment options in clinic). Results are published in Cell Death and Differentiation under the title ‘Thymidylate synthase maintains the de-differentiated state of triple negative breast cancers’ by Siddiqui et al. The research shows the importance of thymidylate catabolism in maintenance of aggressive nature of these tumors. Thymidylate (dTMP) is important for cell proliferation and dividing cells rely on the enzyme called thymidylate synthase for its synthesis. Therefore thymidylate synthase has been an important drug target for many cancers more than half a century now.

The study employed cell culture techniques along with in vivo models to show that changes in the cellular levels of thymidylate synthase can significantly affect tumorigenesis and further connects cellular degradation of dTMP to aggressiveness.

Based on observations, the study postulates that excessively high level of dTMP is produced in these cells which must be disposed of to avoid aberrations in cell cycle. However, the degradation mechanism produces metabolic molecules that fuel aggressiveness in these cells by mechanism that is still unknown. The study provides rationale to investigate thymidylate degradation mechanism in depth, as follow up studies might provide better options for the clinical management of the triple negative breast cancer.