Analysis of gene regulatory networks allows the identification of master transcriptional factors that control specific groups of genes. In this work, we inferred a gene regulatory network from a large dataset of breast cancer samples to identify the master transcriptional factors that control the genes within signal transduction pathways. The focus in a particular subset of relevant genes constitutes an extension of the original Master Regulator Inference Algorithm (MARINa) analysis. This modified version of MARINa utilizes a restricted molecular signature containing genes from the 25 human pathways in KEGG's signal transduction category. Our breast cancer RNAseq expression dataset consists of 881 samples comprising tumors and normal mammary gland tissue. The top 10 master transcriptional factors found to regulate signal transduction pathways in breast cancer we identified are: TSHZ2, HOXA2, MEIS2, HOXA3, HAND2, HOXA5, TBX18, PEG3, GLI2, and CLOCK. The functional enrichment of the regulons of these master transcriptional factors showed an important proportion of processes related to morphogenesis. Our results suggest that, as part of the aberrant regulation of signaling pathways in breast cancer, pathways similar to the regulation of cell differentiation, cardiovascular system development, and vasculature development may be dysregulated and co-opted in favor of tumor development through the action of these transcription factors.

17beta-Estradiol induced LPA(1) receptor desensitization in C9 cells stably expressing LPA(1) receptors and transiently expressing estrogen receptor alpha. Such desensitization was evidenced by a reduction in lysophosphatidic acid-mediated Ca(2+)mobilization and it was associated to receptor phosphorylation and internalization. These effects of 17beta-estradiol were rapid (taking place over 5 min) and were blocked by the estrogen receptor antagonist ICI 182780. Similarly, inhibitors of phosphoinositide 3-kinase (wortmannin and LY294002) and of protein kinase C (staurosporine and Gö 6976) blocked 17beta-estradiol-induced LPA(1) receptor desensitization and phosphorylation. Confocal microscopy evidenced LPA(1) receptor internalization in response to 17beta-estradiol treatment. Association between LPA(1) receptors and protein kinase C alpha was suggested by co-immunoprecipitation assays. Protein kinase C alpha was associated with LPA(1) receptors in the absence of stimulus and such association further increased in a dynamic fashion in response to 17beta-estradiol. The results demonstrated that in C9 cells estrogens modulate LPA(1) action through estrogen receptor alpha with the participation of protein kinase C alpha and phosphoinositide 3-kinase.

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.