Circadian Control of NAD+ as New Antineoplastic Target for Breast Cancer

Breast cancer is unique among human neoplasms because it occurs in a high percentage of women and afflicts individuals in both the prime of their lives and in advanced age. A major focus in understanding the conditions that promote unregulated cancer cell growth has emerged from studies on the interplay between mitochondria (the energy “furnace” of the cell) and the pathway that converts glucose into energy (glycolysis) in the cytoplasm of the cell. New studies from our laboratory have identified a previously unrecognized mechanism by which normal cells regulate the balance between energy production in the mitochondria and cytoplasm that involves ancient cellular checkpoints--the internal circadian clock that maintains energy constancy across the 24 hr light-dark cycle in all tissues and the molecule NAD+. We propose that dysregulation in the balance between mitochondrial and cytoplasmic energy production in breast cancer entails disruption of the circadian clock and the production of NAD+. Indeed, we find altered clock- and NAD+ related gene expression in many human breast cancers that corresponds with survival. Here, we propose to apply genetic- and cell-based approaches to define the therapeutic potential of targeting the fuel utilization and energy production pathway controlled by the clock-NAD+-axis in breast cancer.