C-Terminal Binding Protein: A Molecular Link between Metabolic Imbalance and Epigenetic Regulation in Breast Cancer

The prevalence of obesity has given rise to significant global concerns as numerous population-based studies demonstrate an incontrovertible association between obesity and breast cancer. Mechanisms proposed to account for this linkage include exaggerated levels of carbohydrate substrates, elevated levels of circulating mitogenic hormones, and inflammatory cytokines that impinge on epithelial programming in many tissues. Moreover, recently many scientists have rediscovered the observation, first described by Otto Warburg nearly a century ago, that most cancer cells undergo a dramatic metabolic shift in energy utilization and expenditure that fuels and supports the cellular expansion associated with malignant proliferation. This shift in substrate oxidation comes at the cost of sharp changes in the levels of the high energy intermediate, nicotinamide adenine dinucleotide (NADH). In this review, we discuss a novel example of how shifts in the concentration and flux of substrates metabolized and generated during carbohydrate metabolism represent components of a signaling network that can influence epigenetic regulatory events in the nucleus. We refer to this regulatory process as “metabolic transduction” and describe how the C-terminal binding protein (CtBP) family of NADH-dependent nuclear regulators represents a primary example of how cellular metabolic status can influence epigenetic control of cellular function and fate. 1. Introduction The first written description of breast cancer was recorded in 3000？B.C. as an inscription in the Smith Papyrus that pictured ulcerating lesions of the breast, a condition for which there was no cure [1]. Though, as early as Hippocrates (460–375？BC), the general belief was that cancer initiated from natural causes, a fuller understanding of cancer did not emerge until the late nineteenth century where the development of higher resolution microscopy made the visualization of cells and tissue possible [2]. This event marked the birth of modern pathology and revealed that there are striking differences in the appearance of cancer cells when compared to the surrounding normal tissue. This difference or “otherness” of malignancy made it clear that cancer develops from a change or transformation of normal tissue, a difference that modern molecular biology reveals to be rooted in genomic “changes” or mutation to cellular DNA sequence [3]. It is now widely recognized that mammalian cells are constantly exposed to genotoxic stress from both endogenous and exogenous sources that threaten to change or mutate the human genome and