Abstract
Metabolic transformations have been reported as involved in neoplasms survival. This suggests a role of metabolic pathways as potential cancer pharmacological targets. Modulating tumor's energy production pathways may become a substantial research area for cancer treatment. The significant role of metabolic deregulation as inducing transcriptional instabilities and consequently whole-system failure, is thus of foremost importance. By using a data integration approach that combines experimental evidence for high-throughput genome wide gene expression, a non-equilibrium thermodynamics analysis, nonlinear correlation networks as well as database mining, we were able to outline the role that transcription factors MEF2C and MNDA may have as main master regulators in primary breast cancer phenomenology, as well as the possible interrelationship between malignancy and metabolic dysfunction. The present findings are supported by the analysis of 1191 whole genome gene expression experiments, as well as probabilistic inference of gene regulatory networks, and non-equilibrium thermodynamics of such data. Other evidence sources include pathway enrichment and gene set enrichment analyses, as well as motif comparison with a comprehensive gene regulatory network (of homologue genes) in Arabidopsis thaliana. Our key finding is that the non-equilibrium free energies provide a realistic description of transcription factor activation that when supplemented with gene regulatory networks made us able to find deregulated pathways. These analyses also suggest a novel potential role of transcription factor energetics at the onset of primary tumor development. Results are important in the molecular systems biology of cancer field, since deregulation and coupling mechanisms between metabolic activity and transcriptional regulation can be better understood by taking into account the way that master regulators respond to physicochemical constraints imposed by different phenotypic conditions.
Highlights
It is known that tumors could depend on energy production pathways that are different from those of normal cells
Core regulation genes From the set of differentially expressed genes, data mining techniques were implemented to determine a set of genes that at the same time were involved in metabolic activity at the cell level and/or in cancer; and possess experimental data to accurately determine the parameters involved in our non-equilibrium thermodynamic model
It has been shown that its chromosomal localization is assigned to the so-called mammary cancer susceptibility 1 locus (Mcs1) on chromosome 2q1 segregating with the sensitivity to mammary cancer development in a murine model [39]
Summary
It is known that tumors could depend on energy production pathways that are different from those of normal cells These unique pathways require in some cases the expression and function of so-called tumor-specific enzymes. Some of these glycolytic enzymes, as well as other modulators of tumor behavior, have recently been analyzed in search for a clue that inhibition of such enzymes or appropriate tuning of such modulators should deprive tumors of energy, while leaving non-transformed cells unaffected. Preliminary experiments on animals with hepatocellular carcinoma have shown very encouraging results It appears that modulating the energy production pathways of tumors is poised to become a substantial research area for cancer treatment [2]. It has been discussed how a combination of agents that inhibit both energy production and cell signaling may provide a novel and effective approach to target pancreatic cancer effectively
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