Radiotherapy and breast cancer: finally, an lncRNA perspective on radiosensitivity and radioresistance

Abstract

Radiotherapy (RT) serves as one of the key adjuvant treatments in management of breast cancer. Nevertheless, RT has two major problems: side effects and radioresistance. Given that patients respond differently to RT, it is imperative to understand the molecular mechanisms underlying these differences. Two-thirds of human genes do not encode proteins, as we have realized from genome-scale studies conducted after the advent of the genomic era; nevertheless, molecular understanding of breast cancer to date has been attained almost entirely based on protein-coding genes and their pathways. Long non-coding RNAs (lncRNAs) are a poorly understood but abundant class of human genes that yield functional non-protein-coding RNA transcripts. Here, we canvass the field to seek evidence for the hypothesis that lncRNAs contribute to radioresistance in breast cancer. RT-responsive lncRNAs ranging from "classical" lncRNAs discovered at the dawn of the post-genomic era (such as HOTAIR, NEAT1, and CCAT), to long intergenic lncRNAs such as LINC00511 and LINC02582, antisense lncRNAs such as AFAP-AS1 and FGD5-AS1, and pseudogene transcripts such as DUXAP8 were found during our screen of the literature. Radiation-related pathways modulated by these lncRNAs include DNA damage repair, cell cycle, cancer stem cells phenotype and apoptosis. Thus, providing a clear picture of these lncRNAs' underlying RT-relevant molecular mechanisms should help improve overall survival and optimize the best radiation dose for each individual patient. Moreover, in healthy humans, lncRNAs show greater natural expression variation than protein-coding genes, even across individuals, alluding to their exceptional potential for targeting in truly personalized, precision medicine.

Keywords: breast neoplasms; genomics; long non-coding RNAs; non-coding RNAs; precision medicine; radioresistance; radiosensitivity; radiotherapy.

Figure 1

Major mechanisms of action of long non-coding RNAs in mammalian systems. Gene expression is regulated at three distinct levels - epigenetic (chromatin), transcriptional, and post-transcriptional - by lncRNAs as shown here and as detailed in the main text. (A) guide lncRNA, (B) enhancer RNA, (C) forming a triplex structure with DNA sequence at regulatory regions and interaction with transcription factors to regulate gene expression, (D) lncRNA as scaffold, (E) lncRNA as decoy, (F) lncRNA as sponge for miRNAs, (G) lncRNA-encoded protein, and (H) mRNA:lncRNA hybridization in post-transcriptional sense-antisense pairs. Most of these effects can be classified as epigenetic and transcriptional regulation, as illustrated in the nucleus on the left, or post-transcriptional mechanisms in the cytoplasm, on the right. For details about lncRNA function at the chromatin level, the transcriptional level, and the post-transcriptional level refer to the main text. Created with BioRender.com.

Figure 2

A workflow for integration of all clinical modules in RT, as genomics, lncRNA-inclusive transcriptomics, and radiomics, to identify the most informative radiation responsiveness signature. Longitudinal studies conducted in large cohorts provide the foundation. Associating patient genomics data with radiation response is at the focus of field radiation genomics. Areas dependent on lncRNAs, in view of these transcripts’ abundance, function, and prevalence, include epigenomics, transcriptomics, and proteomics. Correlating radiomics features with patient molecular profiles is the focus of the growing field of imaging genomics. Radiogenomics is a term that should be applicable for both the molecular and the imaging aspects of the field. Created with BioRender.com.