Homocysteine Is an Oncometabolite in Breast Cancer, Which Promotes Tumor Progression and Metastasis

Abstract

Abstract : The goal of this project is to interrogate the role of the amino acid homocysteine in breast cancer progression and metastasis and to test the hypothesis that this amino acid is actually an oncometabolite. According to this hypothesis, homocysteine levels increase in breast cancer, which results in changes in gene expression in tumor cells helping the tumors to grow and metastasize. The molecular basis for the increase in the levels of this amino acid in breast cancer is the downregulation of the enzyme methylene tetrahydrofolate reductase (MTHFR) via DNA methylation. This enzyme is responsible for the conversion of methylene tetrahydrofolate to methyl tetrahydrofolate, which is necessary to convert homocysteine into methionine by serving as a cofactor for methionine synthase. As such, the downregulation of MTHFR in breast cancer reduces the activity of methionine synthase and thus interferes with the conversion of homocysteine into methionine, thus increasing the levels of homocysteine. We hypothesize that homocysteine promotes Wnt/beta-catenin signaling, increases IL-6, TGF-beta, ANGPTL4, and MMP9 expression, thus driving tumor progression at the primary site and also promoting metastasis of the cancer to the lungs.