| Popis: |
Nicotinamide N-methyltransferase (NNMT) methylates nicotinamide (vitamin B3) to convert it into 1-methylnicotinamide (1-MNA) using the universal methyl donor S-adenosylmethionine (SAM) also utilized by DNA and histone methyltransferases. This enzymatic reaction has first been proposed as an excess nicotinamide removal mechanism as 1-MNA is excreted in urine; however, there is now strong literature support for NNMT’s role in regulating hepatocyte/adipocyte cellular metabolism and cancer cell phenotypes through SAM-depletion induced DNA/histone hypomethylation and associated alterations in the expression of metabolic genes and tumor-promoting genes. Here, I report a novel association between triple-negative breast cancer (TNBC) NNMT expression and TNBC gene expression along with in vivo metastatic potential. TNBC is an aggressive disease that comprises approximately 15% of all breast cancers, is uniformly treated with chemotherapy due to lack of ER/PR/HER2 expression and lack of other genetic drivers that commonly occur in the patient population, and therefore has an unmet need for effective targeted therapies. My dissertation research implicates NNMT as a metastasis-promoting protein in TNBC. I report that NNMT expression in TNBC cells is associated with 1) downregulated intracellular SAM levels, 2) upregulated expression of EMT and invasion-promoting genes, 3) downregulated expression of anabolic genes, and 4) increased probability of visceral metastasis formation in xenograft mouse models. I also report that NNMT-depletion in TNBC cells significantly decreases the probability of visceral metastasis formation in vivo while specifically upregulating the liver tropism of TNBC cells. Finally, remainder of my dissertation investigates and discusses NNMT-regulated cellular mechanisms that are pharmacologically targetable along with NNMT to mitigate overall and liver-specific TNBC metastasis formation as a potential therapeutic strategy. |
