TY  - EJOU
AU  - Shakartalla, Sarra B. 
AU  - Talaat, Iman M. 
AU  - Ali, Nival 
AU  - Salih, Shahenaz S. 
AU  - Shareef, Zainab M. Al 
AU  - Alkhayyal, Noura 
AU  - Bendardaf, Riyad 
AU  - Soliman, Sameh S. M. 

TI  - PNP as a Metabolic and Prognostic Driver of Breast Cancer Aggressiveness: Insights from Patient Tissue and Cell Models
T2  - Oncology Research

PY  - 2026
VL  - 34
IS  - 1
SN  - 1555-3906

AB  -  <b>Objectives:</b> Breast cancer (BC) is the leading cause of cancer-related mortality in women, largely due to metastasis. This study aims to explore the role of purine nucleoside phosphorylase (PNP), a key enzyme in purine metabolism, in the aggressiveness and metastatic behavior of BC. <b>Methods:</b> A comprehensive analysis was performed using <i>in silico</i> transcriptomic data (<i>n</i> = 2509 patients), immunohistochemical profiling of BC tissues (<i>n</i> = 103), and validation through western blotting in multiple BC cell lines. Gene expression and survival analyses were conducted using Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis 2 (GEPIA2), and the cBioPortal for cancer genomics (cBioPortal) platforms. Correlations between PNP and key epithelial–mesenchymal transition (EMT) markers, molecular subtypes, tumor grades, and stages were examined. <b>Results:</b> PNP was significantly overexpressed in human epidermal growth factor receptor 2 (HER-2)-positive and triple-negative BCs compared to luminal subtypes. High PNP levels were strongly associated with advanced BC stages, high-grade tumors, EMT phenotypes, and poor overall survival. Notably, HER-2 inhibition suppressed PNP expression, while PNP gene silencing induced HER-2 upregulation, revealing a reciprocal regulatory loop. Dual inhibition of PNP and HER-2 resulted in a significant reduction in cell viability compared to HER-2 inhibition alone. <b>Conclusion:</b> Collectively, PNP emerges as a promising biomarker of BC aggressiveness and progression. Its reciprocal interaction with HER-2 underscores its potential as a therapeutic target. Dual targeting of PNP and HER-2 may offer a novel strategy for improving outcomes in aggressive BC subtypes.
KW  - Purine nucleoside phosphorylase; metastasis; hypoxanthine; breast cancer

DO  - 10.32604/or.2025.070808