@Article{or.2026.078813,
AUTHOR = {Wei Lee, Hung-Yu Lin, Pei-Yi Chu},
TITLE = {Integrated Multi-Omics and Spatial Transcriptomics Reveal GUK1 as a Prognostic Biomarker Regulated by the TP53-HSF1 Axis in Breast Cancer},
JOURNAL = {Oncology Research},
VOLUME = {},
YEAR = {},
NUMBER = {},
PAGES = {{pages}},
URL = {http://www.techscience.com/or/online/detail/27148},
ISSN = {1555-3906},
ABSTRACT = {<b>Background:</b> Guanylate kinase 1 (GUK1) is crucial for nucleotide metabolism, yet its impact on breast cancer (BC) progression remains poorly defined. The objective of the present study is to investigate GUK1 as a prognostic biomarker and therapeutic target. <b>Methods:</b> We employed a multi-omics approach integrating The Cancer Genome Atlas (TCGA) data, machine learning algorithm, High-Definition spatial transcriptomics (Visium HD), single-cell profiling, molecular docking and experimental validation including <i>in vitro</i> knockdown models and Surface Plasmon Resonance (SPR). <b>Results:</b> LASSO regression identified <i>GUK1</i> as a key metabolic driver. High expression correlated significantly with poor survival and was most pronounced in Human Epidermal Growth Factor Receptor 2 (HER2)-positive and triple-negative subtypes. Spatial transcriptomics revealed <i>GUK1</i> strongly colocalizes with expanding cancer cell nests, intensifying with disease stage. Single-cell analysis linked <i>GUK1</i> overexpression to an immunosuppressive microenvironment enriched in exhausted T-cells. Clinically and molecularly, <i>TP53</i> mutations are highly associated with <i>HSF1</i> promoter hypomethylation and subsequent HSF1-mediated GUK1 upregulation. We experimentally confirmed this axis, showing that <i>HSF1</i> or <i>GUK1</i> knockdown significantly impaired cell migration and suppressed mTOR signaling. Furthermore, while high <i>GUK1</i> levels predicted resistance to CDK4/6 inhibitors, they enhanced sensitivity to the PI3K/mTOR inhibitor Apitolisib. This therapeutic vulnerability was validated by SPR, which confirmed high-affinity binding between GUK1 and Apitolisib, and by cell viability assays where <i>GUK1</i> depletion induced drug resistance. <b>Conclusion:</b> GUK1 serves as a robust prognostic biomarker regulated by the TP53-HSF1 axis. Its distinct spatial patterns, immune-suppressive associations, and experimentally validated role in modulating PI3K/mTOR inhibitor sensitivity position GUK1 as a promising target for precision oncology in invasive BC.},
DOI = {10.32604/or.2026.078813}
}