Fig. 6

The TDMD hypothesis may explain the different expression level of hsa-miR-135a-5p between Cluster 2 and Cluster 4. A Schematic representation of the microRNA biogenesis (top panel) and of the two different types of miRNA:target interactions: canonical mechanism (bottom left panel) and TDMD (bottom right panel). MiRNA biogenesis starts in the nucleus, where the enzyme RNA Polymerase II (Pol II) transcripts the miRNA gene into a primary miRNA (pri-miRNA). Next the endonuclease Drosha together with its cofactor DGCR8 cleaves the pri-miRNA into smaller stem-looped structure known as precursor miRNA (pre-miRNA), which is exported to the cytoplasm by the Exportin-5. In the cytosol it is processed by Dicer, a RNAse endonuclease, to form a 21–24 nucleotides long miRNA duplex. The miRNA duplex is then loaded into an Argonaute (AGO) protein to form the miRNA-Induced Silencing Complex (miRISC). Only one strand, the miRNA guide strand, is retained in AGO, while the other strand, known as the passenger strand, is degraded. At this point the miRNA’s fate depends on the degree of complementarity between the miRNA and its target mRNA. A seed-dependent miRNA binding induces the degradation of the mRNA target (canonical mechanism). Conversely, a perfect pairing between the miRNA and its target mRNA characterized by a centered region of few mismatches can induce the degradation of miRNA via TDMD mechanism. B, C Expression levels of the two predicted high confident TDMD targets for hsa-miR-135a-5p (i.e. HMG20A and ZNF135) in Cluster 2 and Cluster 4, measured both in Luminal (B) and in Luminal A (C) cohorts. The transcript expression levels are significantly (Wilcoxon test, p < 0.05) higher in Cluster 2 compared to Cluster 4, according to a potential TDMD mechanism