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

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.