Mounting studies suggest that the protein-coding potential of the human genome is underestimated, and previously unannotated open reading frames (ORFs) have been revealed with technological advances. Although the coding potential of many non-canonical ORFs (ncORFs) is now recognized, their functional prevalence remains to be characterized, partly due to the technical difficulty and labour intensity in screening numerous ncORFs at once. Here, we describe a gain-of-function genomic screen to identify functional ncORF-encoded proteins responsible for breast cancer tumorigenesis. This method is thought to improve the efficiency of characterizing previously neglected ncORFs and reveal potential targets for cancer treatment.
Keywords: Cancer biology; Functional genomic screen; Gain-of-function screen; Micropeptides; Microproteins; Tumorigenesis; ncORF; smORF.
© 2026. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.