Distinct Associations of PTEN and TMPRSS4 Expression with Clinical Outcomes and Fudan Immunohistochemistry-Based Subtypes in Triple-Negative Breast Cancer

Abstract

Triple-negative breast cancer (TNBC) is a heterogeneous and aggressive subtype with limited therapeutic targets. We retrospectively evaluated the expression of phosphatase and tensin homolog (PTEN) and transmembrane serine protease 4 (TMPRSS4) by immunohistochemistry in formalin-fixed, paraffin-embedded tumor tissues from 145 patients with histologically confirmed TNBC, and we analyzed associations with clinicopathological features, Fudan immunohistochemistry-based subtypes, and clinical outcomes. Clinicopathological analyses included all 145 cases. Exploratory survival analyses included 59 patients with complete, verifiable follow-up and outcome data (median follow-up, 46 months), during which three deaths and eight progression events occurred. PTEN-retained expression was associated with worse overall survival (OS; log-rank p = 0.030), whereas TMPRSS4-positive expression was associated with worse progression-free survival (PFS; log-rank p = 0.034). TMPRSS4 expression showed a nominal association with Fudan subtype in the unadjusted omnibus analysis (p = 0.025), which was considered exploratory after Benjamini–Hochberg correction (q = 0.379). The PTEN and TMPRSS4 staining categories were not significantly associated. In an exploratory four-group survival analysis, patients with concurrent PTEN-retained and TMPRSS4-positive expression (PTEN+/TMPRSS4+) showed the lowest OS and PFS estimates, patients with PTEN loss and TMPRSS4 negativity (PTEN−/TMPRSS4−) showed the highest estimates, and the two single-positive groups showed intermediate estimates. Independent transcript-level validation restricted to TNBC in The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) did not reproduce these protein-level associations. These protein-level findings should therefore be considered exploratory and hypothesis-generating and warrant confirmation in larger, adequately powered cohorts using standardized immunohistochemistry with complete treatment data.