USP17L2 is a deubiquitinating enzyme that plays complex roles in cancer biology through regulation of multiple cellular pathways. The protein stabilizes several key substrates by removing ubiquitin conjugates, including SIRT7, which promotes DNA damage repair and chemoresistance in breast cancer cells 1. USP17L2 also deubiquitinates and stabilizes c-Myc, thereby promoting cell proliferation and glycolysis 2. The enzyme regulates transcription factor ELK-1 by removing monoubiquitin from its ETS domain, which augments transcriptional activity and promotes cell proliferation 3. Genomic analysis has identified USP17L2 as part of focal high-level DNA amplifications in breast cancer, with copy number variations detected in circulating cell-free DNA potentially serving as biomarkers for minimal residual disease 4. Hemizygous deletions in USP17L2 have been associated with familial endometriosis, suggesting broader roles in reproductive disorders 5. The dual nature of USP17L2's substrates, which populate both proliferation-promoting and proliferation-inhibiting pathways, may explain conflicting evidence regarding its oncogenic versus tumor suppressor properties 6. These findings position USP17L2 as a potential therapeutic target and prognostic factor in cancer.