Highly connected, non-redundant microRNA functional control in breast cancer molecular subtypes

Abstract

Breast cancer is a complex, heterogeneous disease at the phenotypic and molecular level. In particular, the transcriptional regulatory programs are known to be significantly affected and such transcriptional alterations are able to capture some of the heterogeneity of the disease, leading to the emergence of breast cancer molecular subtypes. Recently, it has been found that network biology approaches to decipher such abnormal gene regulation programs, for instance by means of gene co-expression networks, have been able to recapitulate the differences between breast cancer subtypes providing elements to further understand their functional origins and consequences. Network biology approaches may be extended to include other co-expression patterns, like those found between genes and non-coding transcripts such as microRNAs (miRs). As is known, miRs play relevant roles in the establishment of normal and anomalous transcription processes. Commodore miRs (cdre-miRs) have been defined as miRs that, based on their connectivity and redundancy in co-expression networks, are potential control elements of biological functions. In this work, we reconstructed miR–gene co-expression networks for each breast cancer molecular subtype, from high throughput data in 424 samples from the Cancer Genome Atlas consortium. We identified cdre-miRs in three out of four molecular subtypes. We found that in each subtype, each cdre-miR was linked to a different set of associated genes, as well as a different set of associated biological functions. We used a systematic literature validation strategy, and identified that the associated biological functions to these cdre-miRs are hallmarks of cancer such as angiogenesis, cell adhesion, cell cycle and regulation of apoptosis. The relevance of such cdre-miRs as actionable molecular targets in breast cancer is still to be determined from functional studies.

Oncogenic Role of miR-217 During Clear Cell Renal Carcinoma Progression

“…These results show a clear trend to favor close gene correlations in terms of base pair distance. However, for miR-gene co-expression networks in breast cancer (14,73,74), we did not observe a trend to present more intrachromosomal miR-gene interactions over inter-chromosomal ones. To our knowledge, this is the first time that a bias into the intra-chromosomal miR-gene interactions, in the context of breast cancer, was observed.…”

Loss of long-range co-expression is a common trait in cancer

“…We have shown, for Luminal A and B breast cancer subtypes, that intra-chromosomal communities are not bound by CTCF binding sites and that copy number alterations do not influence co-expressed network communities with a similar differential expression trend (27) nor do they affect intra-cytoband co-expression patterns (63). Our group has also analyzed epigenetic mechanisms in the context of cancer gene co-expression, in particular the role of miRNA regulation, showing that specific miRNA families alter coexpression in genes related to the epithelial-mesenchymal transition (64, 65), they also promote subtype-specific pathways in breast cancer (66), and are associated with progression stage in clear cell renal carcinoma (67). However, these examples come from inter-chromosomal interactions.…”

Methylation-related genes involved in renal carcinoma progression

“…However, the expression of some suppressor genes in cells with high levels of SET decreases, which suggests that methylation is not the only mechanism that regulates gene expression by this protein. This has led researchers to consider other epigenetic factors such as miRNAs and lncRNAs (Drago-García et al, 2017;Fardi et al, 2018;de Anda-Jáuregui et al, 2018;de Anda-Jáuregui et al, 2021;Zamora-Fuentes et al, 2022). Determining which cells have undergone epigenetic changes, ensuring that therapeutic agents maintain their sustainability and their capacity to penetrate the tumor mass and target malignant cells, will increase the clinical success of the treatment (Fardi et al, 2018).…”