miRNAs involved in the regulation of common breast cancer drugs.
In 1993, a gene silencer known as lin-4 was first discovered in Caenorhabditis elegans and demonstrated to be critical for larval development. Lin
miRNAs involved in the regulation of common breast cancer drugs.
In 1993, a gene silencer known as lin-4 was first discovered in Caenorhabditis elegans and demonstrated to be critical for larval development. Lin-4 belongs to a family of signaling molecules known as non-protein coding microRNAs (miRNAs) which are not only highly conserved in humans, but also involved in the fundamental processes of oncogenesis. While miRNAs are not translated to proteins themselves, they are capable of regulating the expression and translation of other genes thus affecting a multitude of biological and pathological pathways as well as those essential to the malignant landscape. The aim of this chapter is to explore the diverse roles of miRNAs in the context of breast cancer. Following a brief overview of miRNA biogenesis, this chapter covers the production of miRNAs by tumor cells and stromal cells, onco-suppressor miRNAs, use as therapeutics, contribution to therapeutic resistance, and finally their emerging role as biomarkers.
- microRNAs (miRs)
- breast cancer epigenetic alteration
- microRNA-based therapy
- miRNA pharmacogenomics
- clinical trials
A gene silencer known as lin-4 was first discovered in Caenorhabditis elegans and demonstrated to be critical for larval development. Lin-4 belongs to a family of signaling molecules known as non-protein coding microRNA (miRNAs) which are not only highly conserved in humans, but also involved in the fundamental processes of oncogenesis. Approximately 2000 miRNAs are present in the human genome. While miRNAs are not translated into proteins themselves, they are implicated in the regulation of 30% of all genes and are thereby capable of regulating the expression and translation of other genes influencing a multitude of biological and pathological pathways. This chapter explores the diverse roles of miRNAs in the most frequent cancer among women in the world: breast cancer (BC). BC impacts 2.1 million women yearly  and it also causes the greatest number of cancer-related deaths among women. Early detection and diagnosis are critical to survival. In the context of BC, miRNAs are dynamically regulated implicating their use in diagnosis, prognosis and tracking of drug efficacy during treatment. Following a brief overview of miRNA biogenesis, this chapter covers the production of miRNAs by tumor cells, onco-suppressor and tumor-suppressor miRNAs, their contribution to therapeutic resistance, therapeutic miRNAs (as well as therapeutics targeting of miRNAs), and finally their emerging role as biomarkers for BC prognosis, treatment responsiveness and efficacy.
2. MiRNA biogenesis and mechanisms of action
Since 1993, researchers have proceeded to learn that miRNAs were of ancient evolutionary origins. Single stranded, non-protein coding miRNAs with genetic suppression activities were found in algae, plants, invertebrates, vertebrates and even viruses. Further characterization has revealed that miRNAs are not only critical for normal human development, but their aberrant expression is associated with diseases such as cancer [7, 8].
The miRNAs are encoded by genetic sequences which may be located within the introns of protein coding genes as well as in the exons and introns of long noncoding RNAs, and even intergenic regions. According to the miRIAD database, 1157 (61.5%) miRNAs are intragenic (169 exonic and 988 intronic) and 724 (38.5%) are intergenic. MiRNA’s are single-stranded RNA transcripts that are transcribed from DNA sequences and are usually around 22 nucleotides in length. They often form distinct secondary folding conformational motifs. Most miRNAs are first transcribed into primary miRNAs (pri-miRNAs) and processed into precursor miRNAs (pre-miRNAs) and mature miRNAs. Usually they bind to the 3′-untranslated region (UTR) of target mRNAs to suppress their target’s expression by inhibiting its translation. However, they can also interact with coding sequences, the 5′UTR and gene promoter regions. Though less common, some are involved in the translation activation and stabilization of target transcripts. Furthermore, the shuttling of miRNAs between different cellular compartments can also control rates of transcription and translation of their targets.
In the canonical pathway of miRNA biogenesis, RNA polymerase II transcribes miRNAs into primary miRNAs (pri-miRNAs) greater than 200 nucleotides long. Pri-mRNAs are then cleaved into pre-mRNAs by the RNAse III enzyme, Drosha with the help of double stranded RNA binding proteins Pasha and DiGeorge Syndrome Critical Region 8 (DGCR8). The 60–70 nucleotides long pre-mRNAs are then exported out of the nucleus and into the cell cytoplasm by exportin-5 and Ran GTPase. Once in the cytoplasm, pre-mRNAs are cleaved by the RNAse III enzyme Dicer which removes hairpin loops resulting in miRNA duplexes composed of a guide strand and a passenger strand. The passenger strand is discarded and the guide strand associates with Argonaute 2 (Ago2) to form the RNA-induced silencing complex (RISC) which brings the miRNA to its target mRNA. A 6–8 nucleotide sequence on the miRNA, referred to as the “seed sequence” locates the corresponding sequence of