Master regulators of signaling pathways coordinate key processes of embryonic development in breast cancer

Abstract

Signal transduction pathways allow cells to respond to environmental cues and can induce intracellular changes. In some contexts, like embryonic development, signal transduction plays crucial roles in cell fate determination and differentiation, while in developed organisms some of this processes contribute in the maintenance of the structural integrity of tissues.Tumor cells are recognized as having deregulated signaling which leads to a series of abnormal behaviors known as the hallmarks of cancer. Although gene regulation is often viewed as the last step in signal transduction, transcriptional regulation of the components of a pathway may impact in the long term deregulation observed in tumors. The study of gene regulatory networks centered around genes of the signal transduction pathways allows the identification of transcriptional regulators with the greatest influence over the signal transduction gene signature, also denominated Master Regulators.In this work we identify, the master regulators that regulate the expression of genes of 25 relevant pathways grouped in KEGG within the category of signal transduction in a breast cancer dataset. For this purpose we implemented a modified MARINa algorithm that identifies, from a network of regulons, those that possess more differentially expressed genes related to the process to be studied. We identified CLOCK, TSHZ2, HOXA2, MEIS2, HOXA3, HAND2, HOXA5, TBX18, PEG3 and GLI2 as the top 10 master regulators of signaling pathways in breast cancer. Nine of them are recognized for taking part in embryonic development associated processes.Individual enrichment GO biological function for each TMR regulons showed to be significantly enriched in embryonic development related processes. Hedgehog signaling pathway was shown as enriched and also highly deregulated. The genes of the HOXA family are shared among most of the TMRs. Overall, this suggests the importance of the aberrant reprogramming of mechanisms present during embryonic development, being coopted in favor of tumor development.

Master Regulators of Signaling Pathways: An Application to the Analysis of Gene Regulation in Breast Cancer

“…DT-C acknowledges the scholarship and financial support provided by the National Council of Science and Technology (CONACyT) and UNAM. This manuscript has been released as a pre-print at BioRxiv (Tapia-Carrillo et al, 2018). DOI: 10.1101/425777.…”