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.

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.

• Publication year

  2026

• Venue

  International Journal of Biological Macromolecules

• Publication date

  2026-03-01

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1016/j.ijbiomac.2026.151211PMID 41794244
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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