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

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.

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.

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.

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.