A Crossroad of microRNAs and Immediate Early Genes (IEGs) Encoding Oncogenic Transcription Factors in Breast Cancer

Abstract

Signaling networks are involved in development, as well as in malignancy of the mammary gland. Distinct external stimuli activate intricate signaling cascades, which culminate in the activation of specific transcriptional programs. These signal-specific transcriptional programs are instigated by transcription factors (TFs) encoded by the immediate early genes (IEGs), and they lead to diverse cellular outcomes, including oncogenesis. Hence, regulating the expression of IEGs is of great importance, and involves several complementary transcriptional and posttranscriptional mechanisms, the latter entails also microRNAs (miRNAs). miRNAs are a class of non-coding RNAs, which have been implicated in regulation of various aspects of signaling networks. Through examination of the basic characteristics of miRNA function, we highlight the benefits of using miRNAs as regulators of early TFs and signaling networks. We further focus on the role of miRNAs as regulators of IEGs, which shape the initial steps of signaling-induced transcription. We especially emphasize the role of miRNAs in buffering external noise and maintaining low basal activation of IEGs in the absence of proper stimuli.

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

“…This time delay between treatment and RNA collection is likely long enough to allow transcription of immediate early genes. Immediate early gene expression has been shown to be induced within minutes following an external stimulus (35). In the MCF7 combination experiments, the majority of the genes with low p-values at time 0 in our data are known immediate early genes (35,36).…”

miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma

“…MiRNAs act as oncogenes or tumor suppressor when they positively or negatively regulate key genes involved in cellular processes associated to tumor genesis or progression [36]. At the same time it has been reported that several known oncogenic pathways promote carcinogenesis by a fine tuning of miRNAs expression, obtained through different mechanisms as regulation of transcription factors [37-39]. …”

The transcriptomic response of cells to a drug combination is more than the sum of the responses to the monotherapies

“…The high concordance of replicates allowed for clear detection of differentially expressed genes (DEGs) in different conditions ( Figure S3A). To determine DEGs in MCF7, we selected a false discovery rate (FDR) cutoff at which the only DEGs at time 0 (~30 min post-treatment; see Methods) over all treatments are well-known immediate early genes (Sas-Chen, Avraham, & Yarden, 2012;Tullai et al, 2007) ; Table S1). We then used this cutoff across all time points and treatments of the fixed dose experiments.…”

“…This time delay between treatment and RNA collection is likely long enough to allow transcription of immediate early genes. Immediate early gene expression has been shown to be induced within minutes following an external stimulus (Sas-Chen et al, 2012) . In the MCF7 combination experiments, the majority of the genes with low p-values at time 0+ in our data are known immediate early genes (Sas-Chen et al, 2012;Tullai et al, 2007) .…”

“…Immediate early gene expression has been shown to be induced within minutes following an external stimulus (Sas-Chen et al, 2012) . In the MCF7 combination experiments, the majority of the genes with low p-values at time 0+ in our data are known immediate early genes (Sas-Chen et al, 2012;Tullai et al, 2007) . We selected an FDR cutoff of 1.0e-18 for differential expression ( Figure S3A), at which the only DEGs at time 0+ over all treatments are well-known immediate early genes (Table S1).…”