miRNAs versus oncogenes: the power of social networking

microRNAs (miRNAs) are small, non-coding RNAs that regulate the expression of proteins through specific target sites in the corresponding transcripts.These small RNAs may function as oncogenes or tumor suppressors by modulating the levels of critical proteins, and their relevance in human disease and therapy is now under intense investigation.The human genome encodes about 1500 miRNAs that are thought to regulate more than 30% of protein-coding genes.Individual miRNAs can target multiple genes and each protein-coding gene can be regulated by several miRNAs, making the analysis of these networks difficult to explore.In a recent article published in Molecular Systems Biology, Uhlmann et al (2012) report a combined strategy to analyze the multiple miRNAprotein interactions that regulate cell proliferation in response to epidermal growth factor receptor (EGFR), an oncogenic pathway highly relevant in breast cancer.This analysis provides an unprecedented view of the combinatorial effort of miRNAs to control a signaling pathway at different levels.As oncogenic pathways are often resistant to the inhibition of individual regulators, this analysis also provides the molecular basis for selecting individual miRNAs, or a set of a few miRNAs, whose combined activity may be strong enough to treat breast tumors.Activation of the EGFR drives a signaling network that can lead to cell proliferation, survival, angiogenesis, invasion and metastasis.Aberrant expression or activity of EGFR has been strongly linked to the etiology of several human epithelial cancers, including lung, colorectal and breast cancer, among others (Wheeler et al, 2010).Not surprisingly, the EGFR pathway is probably the most explored next-generation target for breast cancer therapy, and several downstream signal transducers, such as RAS, AKT or CDKs, are also currently considered as cancer targets (Weickhardt et al, 2010;Wheeler et al, 2010).The EGFR pathway controls the expression of several miRNAs (Avraham et al, 2010;Garofalo et al, 2011), and some transcription factors and cell cycle regulators downstream of EGFR are known to be regulated by miRNAs at different levels (Avraham et al, 2010; Bueno and Malumbres, 2011).However, current information is scarce and typically describes single interactions between a miRNA and a relevant target transcript.Uhlmann et al (2012) used a genome-wide library of miRNA mimics to test their effect on the expression of 26 proteins in the EGFR-driven cell cycle pathway using reverse-phase protein arrays.Their findings validated some of