Targeting NNMT to Inhibit Obesity-Associated Breast Cancer Development and Progression
Abstract
Triple-negative breast cancer (TNBC), which lacks ERalpha, PR, and HER2 expression, is a 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, a growing problem worldwide, is an important risk factor for at least 15 types of cancers, including breast cancer (BCa). While obesity is associated with worse disease-free survival in all BCa subtypes, obesity increases the incidence and progression in premenopausal TNBC, particularly in non-Hispanic Black women. Clinical studies indicate that obesity exacerbates metastatic progression, as obese patients with BCa are up to 46% more likely to develop distant metastases 10 years after diagnosis. Furthermore, obese patients often develop drug-resistance due to release by fat cells (adipocytes) of inflammatory and adipokine factors that stimulate tumor growth. The overarching goal of this proposal is to identify a unifying determinant that is critical for the growth and metastasis of TNBC and the function of fat cells in order to develop novel interventions to treat TNBC and obesity simultaneously. Driven by oncogene activation or loss of tumor suppressor gene activity, malignant cells often produce large amounts of reactive oxygen species (ROS) owing to their highly proliferative nature. Similarly, an increased ROS level in fat cells is also required to initiate a well-orchestrated cascade in activating insulin signaling, increasing glucose uptake and enhancing rapid lipid synthesis during fat accumulation (lipogenesis). ROS are molecules that contain oxygen; they can easily react with and cause damage to DNA, RNA, and proteins, resulting in cell death and tissue damage. Increasing cellular ROS levels contributes to oxidative stress associated with many pathological states, including aging, neurodegeneration, and inflammation. It remains a mystery how TNBC and fat cells counteract ROS upsurge without compromise to their increased metabolism during growth and fat accumulation. Discovered as a cozymase necessary for fermentation, nicotinamide adenine dinucleotides (NAD+ and NADP+), are the backbone of the cellular defense machinery to remove ROS. Nicotinamide (NAM, also known as Vitamin B3), from either food uptake or cellular recycle of NAM, is the precursor for NAD+ and NADP+ biosynthesis. NAD+/NADH, existed in oxidized (+) or reduced form (H), is involved in the breakdown of dietary sugars, proteins, and fats with the concomitant release of energy needed for cell growth and proliferation; whereas NADP+/NADPH is central to removal of cellular ROS and promotes lipid synthesis, such as fatty acid and cholesterol, that are required for cell division and fat accumulation (energy storage). Recently, we found that nicotinamide N-methyltransferase (NNMT), which is a key enzyme that regulates NAD+ and NADP+ biosynthesis, is robustly expressed in TNBC and fat cells during their growth. Elimination or knockout (KO) of NNMT inhibits TNBC cell growth, and also stops fat accumulation in fat cells and prevents high-fat diet (HFD)-induced obesity in mice. Further mechanistic analyses indicate that NNMT-KO disrupts the redox balance and promotes lipid loss in TNBC and fat cells. Consistent with these observations, our newly developed NNMT-specific inhibitor showed high potency in suppressing TNBC cell growth and fat accumulation in fat cells. Thus, we hypothesize that NNMT is a crucial regulator that maintains redox and lipid balance in TNBC and fat cells. Targeting NNMT with our new inhibitor represents an appealing strategy to achieve a two birds with one stone effect in preventing both TNBC and obesity development simultaneously. Guided by strong preliminary data, we will test this hypothesis by pursuing three specific aims: (1) to determine how NNMT promotes NAD+ and NADP+ biosynthesis in TNBC and fat cells; (2) to
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311010
Entities
People
- Rong Huang
Organizations
- Purdue University
- United States Army