Fatemeh Yazarlou ^1* Ivan Martinez ² Leonard Lipovich ^3,4,5

• ¹ Center for Childhood Cancer, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Georgia, United States
• ² Department of Microbiology, Immunology and Cell Biology, School of Medicine, West Virginia University, Morgantown, West Virginia, United States
• ³ Department of Biology, College of Science, Mathematics and Technology, Kean University-Wenzhou, Wenzhou, Zhejiang Province, China
• ⁴ Shenzhen Huayuan Biological Science Research Institute, Shenzhen Huayuan Biotechnology Co. Ltd., Shenzhen, Guangdong Province, China
• ⁵ Center for Molecular Medicine and Genetics, School of Medicine, Wayne State University, Detroit, Michigan, United States

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 (CSCs) 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 proteincoding genes, even across individuals, alluding to their exceptional potential for targeting intruly personalized, precision medicine.