The evidence of a link between obesity and diabetes and increased mortality from breast cancer is incontrovertible 41–44
. An important feature of the dysfunctional energetics associated with obesity and diabetes and malignant transformation, is elevated carbohydrate metabolism, a central component of the Warburg Effect 45, 46
. This elevated level of carbohydrate metabolism, whether due to the over-nutrition of obesity or the Warburg Effect of cancer bioenergetics, results in increased levels of NADH 47–49
. In this study we propose CtBP is a key downstream epigenetic effector of elevated NADH. Therefore through CtBP, changes in cellular metabolic status can drive genome-wide changes in chromatin through targeted recruitment of CtBP that facilitates the acquisition of epigenetically reprogrammed properties that promote genome instability, dedifferentiation, and the transformation to a more mesenchymal phenotype.
Though this study provides one of the first to profile the binding of CtBP throughout the mammalian genome; how, when, and where the different CtBP complexes target and coordinate the recruitment of specific chromatin modifiers, and their subsequent effect on the epigenome remain to be defined. These epigenetic networks and programs are likely to differ by cellular process and cell type and are likely to reflect a hierarchy of CtBP complexes formed under specific cellular conditions and environments as we have seen in comparing the mesenchymal MDA-MB-231 cell line, with the luminal MCF-7 (, and ). This difference has been demonstrated in prior studies where loss of CtBP had a much great effect on mitotic fidelity in MDA-MB-231 than MCF-7 50
. Future studies to correlate global alterations in histone and DNA modification with changes in CtBP levels (via either genetic or metabolic disruption) in multiple breast cancer subtypes will be necessary to better define the mechanism underlying these differences.
Approximately 5–10% of breast cancers are secondary to inherited mutations of cancer predisposing genes. It is striking that, of the known and newly identified breast cancer predisposing genetic mutations, a substantial number are targeted for repression by CtBP, including PALB2
. Thus the observation that many patients develop breast cancers with features of inherited disease without demonstrating mutation in genes characteristic of the disease 51
, is consistent with a role played by CtBP-regulated pathways in such tumors. Notably, decreased expression specifically of DNA repair proteins is associated with shortened time to recurrence in triple-negative breast cancer 52
. This is consistent with the demonstration, in this current study, of the impact of CtBP targeting on genome stability. Nearly one third of the Fanconi Anemia complementation group is targeted by CtBP. Therefore, it is not surprising that loss of CtBP expression or function results in a significant improvement in DNA repair in breast cancer cell lines (see , and ). Most importantly, targeting by CtBP suggests that these hereditary risk factors for breast cancer may be worsened by lifestyle factors influencing metabolic imbalance.
Finally, many of the new driver mutations identified by recent systematic sequencing of cancer genomes has uncovered several genes with functional roles in epigenetic regulation 53
. CtBP represents a novel class of versatile, multi-potent epigenetic regulators that is likely to play many different roles in cancer etiology and progression. The finding that MTOB can act as a small molecular inhibitor that can reverse genomic targeting by CtBP, provides a proof of principle that pharmacological manipulation of CtBP is feasible. Thus epigenetic targeting through CtBP promises to be a new and exciting area of future therapeutic intervention. New efforts will have to be directed at finding compounds that will function in the nanomolar to micromolar range. Given that weight gain and obesity represent modifiable cancer risk factors linked to lifestyle, a better understanding of CtBP will fuel new ideas and creative strategies for combined behavioral and therapeutic approaches to cancer treatment and prevention.