PTEN Loss in Triple-Negative Breast Cancer: Integrative Molecular and Clinicopathological Insights

Phosphatase and tensin homolog (PTEN) is a key tumor suppressor gene that negatively regulates the PI3K/AKT pathway. PTEN deficiency is the most frequent molecular alteration in triple-negative breast cancer (TNBC); however, the relationship between PTEN protein loss and underlying genomic alterations remains incompletely understood.

Fifty TNBC cases were evaluated for PTEN protein expression by immunohistochemistry on tissue microarrays. PTEN hotspot mutations (Exons 1, 5, 7, and 9) were analyzed using Sanger sequencing, whereas copy number alterations were assessed by multiplex ligation-dependent probe amplification (MLPA) assay. PTEN alterations were correlated with clinicopathological characteristics. External validation of PTEN mRNA and protein expression and prognostic significance was performed using publicly available TCGA/CPTAC datasets and Kaplan-Meier plotter.

PTEN protein loss was observed in 41/50 TNBC cases (82%), indicating that PTEN deficiency is a frequent event in this subtype. PTEN mutations were detected in six cases (12%) and were confined exclusively to Exon 5, comprising one missense mutation (c.277C>A) and two truncating mutations (c.430del and c.433del). MLPA identified PTEN copy number alterations in four cases (8%), including heterozygous deletions and duplications. No significant association was observed between PTEN protein expression and genomic alterations, highlighting a substantial genotype-phenotype discordance. Analysis of independent public datasets confirmed significantly reduced PTEN mRNA and protein expression in TNBC compared with luminal and HER2-positive breast cancers. Patients with low PTEN expression showed a trend toward shorter overall survival (23.5 vs. 38.9 months), though the difference did not reach statistical significance.

PTEN protein loss is highly prevalent in TNBC but is only partially explained by mutations and copy number alterations, suggesting that additional regulatory mechanisms, such as epigenetic or posttranscriptional events, contribute to PTEN inactivation. These findings underscore the biological importance of PTEN deficiency in TNBC and support further investigation of PTEN as a potential prognostic biomarker and therapeutic target.