Circulating microRNAs in breast cancer: novel diagnostic and prognostic biomarkers

Abstract

Effective management of breast cancer depends on early diagnosis and proper monitoring of patients' response to therapy. However, these goals are difficult to achieve because of the lack of sensitive and specific biomarkers for early detection and for disease monitoring. Accumulating evidence in the past several years has highlighted the potential use of peripheral blood circulating nucleic acids such as DNA, mRNA and micro (mi)RNA in breast cancer diagnosis, prognosis and for monitoring response to anticancer therapy. Among these, circulating miRNA is increasingly recognized as a promising biomarker, given the ease with which miRNAs can be isolated and their structural stability under different conditions of sample processing and isolation. In this review, we provide current state-of-the-art of miRNA biogenesis, function and discuss the advantages, limitations, as well as pitfalls of using circulating miRNAs as diagnostic, prognostic or predictive biomarkers in breast cancer management.

Figure 1

Schema depicting miRNA biogenesis and function. Primary miRNA transcript (pri-miRNA) is transcribed by RNA polymerase II/III in the nucleus, forming an elongated RNA hairpin structure that is subsequently cleaved by Drosha into a small stem-loop structure of ~70 nt, (pre-miRNA). Pre-miRNA is exported from the nucleus into the cytoplasm by exportin-5 and the loop is cleaved after the pre-miRNA is loaded onto Dicer, producing a double-stranded structure of miRNA and antisense miRNA*. The latter is typically degraded, whereas the long (~22 nt) mature miRNA strand is incorporated into the miRNA-induced silencing complex (mRISC), leading to mRNA degradation or translational repression. Mature miRNA levels are regulated via binding to ceRNAs such circular (c)RNAs, pseudogenes, and lncRNAs, which act as a sponge to prevent miRNA binding to target mRNAs

Figure 2

Transcriptome–miRNA interaction networks in breast cancer. Schematic representation of the interaction of commonly altered miRNAs in breast cancer and their identified mRNA targets regulating EMT/metastasis, stemness, growth and survival of breast cancer cells. ↑ indicated miRNA or gene is upregulated, whereas (↓) indicate miRNA or gene is downregulated in BC tissue. Yellow filled miRNA ovals indicate miRNAs whose expression is also altered in the circulation based on current review. RHOC, Ras homolog family member C; HOXD10, homeobox D 10; KLF4, Kruppel-like factor 4; PDCD4, programmed cell death 4; SOX4, SRY (sex-determining region Y)-box 4; TNC, Tenascin-C; FHOD1, Formin homology 2 domain containing 1; PPM1F, protein phosphatase, Mg2+/Mn2+ Dependent 1F; ZEB1, zinc-finger E-box binding homeobox 1; ZEB2, zinc-finger E-box binding homeobox 2; VEGFA, vascular endothelial growth factor A; LIN28B, Lin-28 homolog B; RAS, RAS viral oncogene homolog; HMGA2, high mobility group AT-Hook 2; BMI1, BMI1 proto-oncogene, polycomb ring finger; ID4, inhibitor of DNA binding 4, HLH protein; PTEN, phosphatase and tensin homolog; BRCA1, BRCA1, DNA repair associated; BCL2, BCL2, apoptosis regulator; SIRT1, sirtuin 1; ERBB3, Erb-B2 receptor tyrosine kinase 3

Figure 3

Sources and forms of circulating miRNAs. MiRNAs can be released via an active process in the form of exosomes (<100 nM) through the course of exocytosis (a process that involves fusion of the multivesicular body (MVBs) with the plasma membrane) or as microvesicles (100–1000 nM, through outward budding from the plasma membrane). Alternatively, miRNAs can be released as a result of necrosis or apoptosis (programmed cell death). Cell-free circulating miRNAs usually exist bound to ribonucleoprotein complexes (such as Argonaute-2), or high-density lipoprotein (HDL). Circulating miRNAs are also found within lipid microvesicles and exosomes