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ARTICLE

PNP as a Metabolic and Prognostic Driver of Breast Cancer Aggressiveness: Insights from Patient Tissue and Cell Models

Sarra B. Shakartalla1,2,3, Iman M. Talaat1,2,4,*, Nival Ali1, Shahenaz S. Salih1,5, Zainab M. Al Shareef1,2, Noura Alkhayyal6, Riyad Bendardaf2,7,*, Sameh S. M. Soliman1,8,*
1 Research Institute for Medical and Health Sciences, University of Sharjah, Sharjah, 27272, United Arab Emirates
2 College of Medicine, University of Sharjah, Sharjah, 27272, United Arab Emirates
3 Faculty of Pharmacy, University of Gezira, Wadmedani, 21111, Sudan
4 Faculty of Medicine, Alexandria University, Alexandria, 21131, Egypt
5 College of Medical Laboratory Sciences, Sudan University of Science and Technology, Khartoum, 11111, Sudan
6 Histopathology and Laboratory Medicine Department, University Hospital Sharjah, Sharjah, 72772, United Arab Emirates
7 Medical Oncology Unit, University Hospital Sharjah, Sharjah, 72772, United Arab Emirates
8 College of Pharmacy, University of Sharjah, Sharjah, 27272, United Arab Emirates
* Corresponding Author: Iman M. Talaat. Email: email; Riyad Bendardaf. Email: email; Sameh S. M. Soliman. Email: email
(This article belongs to the Special Issue: Discover Biomarkers for Personalized Oncology)

Oncology Research https://doi.org/10.32604/or.2025.070808

Received 24 July 2025; Accepted 14 October 2025; Published online 28 November 2025

Abstract

Objectives: 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. Methods: A comprehensive analysis was performed using in silico transcriptomic data (n = 2509 patients), immunohistochemical profiling of BC tissues (n = 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. Results: 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. Conclusion: 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.

Keywords

Purine nucleoside phosphorylase; metastasis; hypoxanthine; breast cancer

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