Underexplored reciprocity between genome-wide methylation status and long non-coding RNA expression reflected in breast cancer research: potential impacts for the disease management in the framework of 3P medicine

Abstract

Breast cancer (BC) is the most common female malignancy reaching a pandemic scale worldwide. A comprehensive interplay between genetic alterations and shifted epigenetic regions synergistically leads to disease development and progression into metastatic BC. DNA and histones methylations, as the most studied epigenetic modifications, represent frequent and early events in the process of carcinogenesis. To this end, long non-coding RNAs (lncRNAs) are recognized as potent epigenetic modulators in pathomechanisms of BC by contributing to the regulation of DNA, RNA, and histones' methylation. In turn, the methylation status of DNA, RNA, and histones can affect the level of lncRNAs expression demonstrating the reciprocity of mechanisms involved. Furthermore, lncRNAs might undergo methylation in response to actual medical conditions such as tumor development and treated malignancies. The reciprocity between genome-wide methylation status and long non-coding RNA expression levels in BC remains largely unexplored. Since the bio/medical research in the area is, per evidence, strongly fragmented, the relevance of this reciprocity for BC development and progression has not yet been systematically analyzed. Contextually, the article aims at:consolidating the accumulated knowledge on both-the genome-wide methylation status and corresponding lncRNA expression patterns in BC andhighlighting the potential benefits of this consolidated multi-professional approach for advanced BC management. Based on a big data analysis and machine learning for individualized data interpretation, the proposed approach demonstrates a great potential to promote predictive diagnostics and targeted prevention in the cost-effective primary healthcare (sub-optimal health conditions and protection against the health-to-disease transition) as well as advanced treatment algorithms tailored to the individualized patient profiles in secondary BC care (effective protection against metastatic disease). Clinically relevant examples are provided, including mitochondrial health control and epigenetic regulatory mechanisms involved.

Keywords: Biomarker panels; Breast cancer; Endothelin-1; Epigenetic modifications; Health policy; Health-to-disease transition; Homocysteine; Improved healthcare economy; Metastatic disease; Methylation; Mitochondria; Non-coding RNAs; Phenotyping; Population screening; Pre/clinical studies; Predictive preventive personalized medicine (PPPM/3PM); Primary and secondary care; Suboptimal health; lncRNAs.

Fig. 1

A Genome vs transcriptome, and ncRNAs vs protein-coding RNAs. B Essential functions of lncRNAs in the cell. C The roles of lncRNAs in breast cancer. A Most of the mammalian genome is actively transcribed. However, non-coding RNAs, formerly called “transcriptional noise” or “junk,” form a substantial part of the transcriptome. Besides, less than 2% of the transcripts code for proteins. B Long non-coding RNAs forming the most prevalent and diverse class of regulatory ncRNAs are linked to different cellular functions, including gene activation, chromatin modification and remodeling, scaffold for protein complex, shorter ncRNAs generation, mRNA regulation and suppression, and miRNA sponges. C Numerous lncRNAs participated in regulating different stages of breast cancer, for example, cell cycle progression, proliferation and apoptosis, migration, invasion, metastasis, EMT, drug resistance, genomic instability, or breast cancer stem cells. LncRNAs acted as either promoters or inhibitors of the abovementioned key processes associated with breast carcinogenesis [, , –32]

Fig. 2

Schematic representation of a classification of non-coding RNAs based on their structure, function, length, genomic location, mechanism of action, and effects on DNA, emphasizing long non-coding RNAs; NcRNAs can be divided into linear or circular. According to their function, ncRNAs are recognized as housekeeping or regulatory. Housekeeping ncRNAs are constitutively expressed in each cell type, required for their viability and primarily regulating generic and essential functions of cells. The regulatory ncRNAs act as key regulators of various RNA molecules and gene expression at the epigenetic, transcriptional, and post-transcriptional levels. Based on their length, ncRNAs can be divided into small or long. LncRNAs can be genomically located between two protein-coding genes (intergenic lncRNAs), in an intron of a coding region (intronic lncRNAs), or within 1 kb of promoters and transcribed from the same promoter as a protein-coding gene yet in the opposite direction (bidirectional lncRNAs). Other lncRNAs can be transcribed either from the sense RNA strand of the protein-coding genes (sense lncRNAs) or the antisense RNA strand of a protein-coding gene (antisense lncRNA) might overlap one or several introns and/or exons. According to the mechanism of action, lncRNAs can be divided into four groups—signal, decoy, guide, and scaffold. Signal lncRNAs, with regulatory function, are expressed at a specific time and in a particular position in the cell as a response to stimuli. Signal lncRNAs can mediate the transcription of downstream genes alone or in combination with other proteins. Decoy lncRNAs can indirectly repress transcription, either binding to some functional proteins and blocking them from regulating DNA and mRNA or binding to miRNA competitively with mRNA and blocking the inhibitory effect of miRNA on mRNA. Guide lncRNAs are necessary to organize and locate some functional proteins at specific genomic loci to perform their functions. Scaffold lncRNAs are important in assembling multi-protein complexes in the target area. Moreover, lncRNAs can mediate epigenetic regulation via chromatin-modifying proteins in cis or trans manner. Cis-acting lncRNAs affect target genes located near the lncRNA gene on the same chromosome, while trans-acting lncRNAs affect target genes situated distal to the lncRNA gene, often in a different chromosome [, , , , –, –51]; Abbreviations used: crasiRNA, centromere repeat associated small interacting RNA; miRNA, microRNA; ncRNAs, non-coding RNAs; piRNA, piwi RNA; rRNA, ribosomal RNAs; siRNA, small interfering RNA; snoRNA, small nucleolar RNA; snRNA, small nuclear RNA; tRNA, transfer RNA; tsRNA, tRNA-derived small RNAs