An integrative multi-omics analysis leveraging Mendelian randomization and subsequent experimental validation prioritizes glutathione S-transferase mu 5 (GSTM5) as a genomic stability-related gene and a therapeutic vulnerability to PLK1 inhibition in breast cancer
- Int J Biol Macromol. 2026 Apr:353:151211. doi: 10.1016/j.ijbiomac.2026.151211.
- 1. Department of Breast Surgery, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
- 2. Department of Endocrine, The 900th Hospital of Joint Logistic Support Force, The Chinese People's Liberation Army (PLA), Fuzhou, 350001, China.
- 3. Department of Breast Surgery, Shanghai Baoshan Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, 201900, China.
- 4. Medical school of Chinese PLA, Chinese PLA General Hospital, Beijing, 100853, China. Electronic address: [email protected].
- 5. Department of Breast Surgery, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. Electronic address: [email protected].
Circadian rhythm disruption has been associated with increased breast Cancer risk, yet the underlying molecular drivers remain unclear. Here, we applied an integrative multi-omics framework for genetic prioritization across blood and breast tissue datasets, coupled with independent experimental validation, to systematically identify functional candidates from a pre-specified circadian rhythm-related gene set. This strategy identified Glutathione S-transferase mu 5 (GSTM5) as the sole candidate gene meeting our stringent criteria, yielding robust genetic evidence suggesting a protective association against breast Cancer across multiple independent datasets. In breast tumors, GSTM5 downregulation was accompanied by promoter-proximal hypermethylation, and low GSTM5 expression was associated with markers of genomic instability. In bulk cohorts, prognostic and microenvironmental associations were context-dependent and intertwined with clinicopathologic subtypes. Functionally, GSTM5 depletion impaired DNA damage repair following irradiation, and GSTM5-low breast Cancer cells were preferentially sensitive to Polo-like kinase 1 (PLK1) inhibition. Collectively, these findings implicate GSTM5 deficiency in genomic instability and support further evaluation of PLK1 inhibition as a biomarker-informed therapeutic hypothesis in breast Cancer.