Targeting NNMT to Inhibit Obesity-Associated Breast Cancer Development and Progression

Summary: Triple-negative breast cancer (TNBC) is the most aggressive disease noted for the development of recurrence, distant metastases and short survival times, particularly and tragically in young women. Although the etiology of TNBC remains unclear, obesity, an escalating problem worldwide, is an important risk factor for the initiation and progression of TNBC, particularly in non-Hispanic Black (NHB) women. The overarching goal of this proposal is to identify a common molecule that is not only critical for the initiation and progression of TNBC but also essential for adipocyte function in order to develop novel intervention to prevent TNBC and obesity together. Recently we found that nicotinamide N-methyltransferase (NNMT) is robustly expressed in TNBC cells detached from matrix and in adipocytes during adipogenesis. Knockout (KO) of NNMT not only inhibits TNBC cell growth but also stops adipocyte adipogenesis and prevents high-fat diet (HFD)-induced obesity. Further mechanistic analyses indicate that NNMT-KO disrupts redox balance and promotes lipid loss in TNBC cells and adipocytes. Consistent with these observations, a newly developed NNMT bisubstrate inhibitor from us, showed high specificity and efficacy in suppressing TNBC cell growth and adipocyte adipogenesis. Thus, we hypothesize that NNMT is a crucial regulator to maintain redox balance and lipid homeostasis in TNBC cells and adipocytes. Targeting NNMT with our new specific inhibitor represents an appealing strategy to achieve a “one stone two birds” effect in preventing both TNBC progression and obesity development simultaneously. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: 1) to define how the NNMT-CHAC1 axis represses ROS by increasing NAD(P)+ and GSH levels; 2) to delineate how NNMT regulates lipid metabolism in TNBC and adipocytes; and 3) to determine the efficacy of NNMT specific inhibitor in treating obesity-associated TNBC. We will utilize a wide variety of innovative, complementary and systematic methods to vigorously validate the central hypothesis and achieve the goals of this study. This is multiple PI project combines the Zhou laboratory’s strength in TNBC research with the Huang laboratory’s expertise in drug discovery and medicinal chemistry. Our proposal is innovative and significant, because NNMT represents the achilles heel of TNBC cells and adipocytes; targeting this key molecule offers an effective strategy to prevent the initiation and progression of obesity-associated TNBC.