Lacey Foster, a junior biology major at Spelman College, worked to validate genetic dependencies in metastatic breast cancer.
Metastasis is responsible for the majority of breast cancer-related mortality. Through systematic testing of breast cancer cell lines in vivo, we have identified a strong correlation between metastatic potential and genetic dependency on Dihydroorotate dehydrogenase (DHODH), an inter-mitochondrial gene required for de novo pyrimidine biosynthesis. The Broad provides a uniquely diverse and collaborative scientific environment. Students are given an amazing opportunity to work at the cutting edge of science, among giants across scientific disciplines. I benefited greatly from the intentional and holistic mentorship I received across the institute. This experience has truly fostered my own creativity and innovation as I carve the path for my scientific future.We determined the consequences of pharmacologic inhibition of DHODH in breast cancer with Brequinar, a small molecule inhibitor of DHODH. During short-term drug treatments, Brequinar decreased cell viability at high concentrations in metastatic cell lines but was insufficient to completely eliminate cells. During long-term drug treatments, we have found Brequinar to be more effective at killing cells at lower concentrations. In addition, we utilized CRISPRi and CRISPR knockout technology to target and regulate the expression of DHODH. By identifying the potential effects of DHODH inhibition, we are working towards a more holistic understanding of the genes that breast cancer is most reliant on and determining potential directions for treatments.
Project: DHODH dependency in highly metastatic breast cancer
Mentors: Xin Jin and Todd Golub, Cancer Program