Breast cancer and microRNAs: therapeutic impact.

Despite advances in detection and therapies, breast cancer is still the leading cause of cancer death in women worldwide. The etiology of this neoplasm is complex, and both genetic and environmental factors contribute to the complicate scenario. Gene profiling studies have been extensively used over the last decades as a powerful tool to define the signature of different cancers and to predict outcome and response to therapies. More recently, a new class of small (19-25 nucleotides) non-coding RNAs, microRNAs (miRs or miRNAs) has been linked to several human diseases, included cancer. MicroRNAs are involved in temporal and tissue-specific eukaryotic gene regulation,(1) either by translational inhibition or exonucleolytic mRNA decay, targeted through imperfect complementarity between the microRNA and the 3' untranslated region (3'UTR) of the mRNA.(2) Since their ability to potentially target any human mRNA, it is likely that microRNAs are involved in almost every biological process, including cell cycle regulation, cell growth, apoptosis, cell differentiation and stress response.(3) The involvement of microRNAs in the biology of human cancer is supported by an increasing body of experimental evidence, that has gradually switched from profiling studies, as the first breast cancer specific signature reported in 2005 by our group(4) describing an aberrant microRNA expression in different tumor types, to biological demonstrations of the causal role of these small molecules in the tumorigenic process, and the possible implications as biomarkers or therapeutic tools.(5) These more recent studies have widely demonstrated that microRNAs can modulate oncogenic or tumor suppressor pathways, and that, at the same time, their expression can be regulated by oncogenes or tumor suppressor genes. The possibility to modulate microRNA expression both in vitro and in vivo by developing synthetic pre-microRNA molecules or antisense oligonucletides has at the same time provided a powerful tool to a deeper comprehension of the molecular mechanisms regulated by these molecules, and suggested the intriguing and promising perspective of a possible use in therapy. Here we review our current knowledge about the involvement of microRNAs in cancer, focusing particularly on breast cancer, and their potential as diagnostic, prognostic and therapeutic tools.