Integrated Assessment of HIF-1α and SOD2 Expression and Their Prognostic Implications in Triple-Negative Breast...

Triple-negative breast cancer (TNBC) is characterized by aggressive clinical behavior and limited targeted therapeutic options. Hypoxia signaling mediated by hypoxia-inducible factor-1α (HIF-1α) and mitochondrial antioxidant defense driven by superoxide dismutase 2 (SOD2) represent biologically interconnected stress-adaptation pathways that may contribute to tumor progression. However, their combined prognostic impact in TNBC remains insufficiently defined. This retrospective study included 70 patients with surgically treated TNBC. Immunohistochemical expression of HIF-1α (nuclear) and SOD2 (cytoplasmic) was semi-quantitatively scored and analyzed individually and in combination. Patients were stratified as both-low, single-high, or both-high expression. Associations with clinicopathological parameters were evaluated, and overall survival (OS) and disease-free survival (DFS) were analyzed using Kaplan-Meier and Cox regression models. Stage-adjusted and stage-free multivariable analyses were performed, and sensitivity analyses using penalized Cox regression were conducted. High SOD2 expression was observed in 68.6% and high HIF-1α expression in 24.3% of cases. Neither marker was independently associated with survival outcomes in Kaplan-Meier or multivariable analyses. HIF-1α-high tumors showed a nominally lower Ki-67 proliferation index compared with HIF-1α-low tumors (median 30.0% vs. 60.0%, p = 0.023); however, given the number of comparisons performed, this finding should be regarded as exploratory and interpreted cautiously. Advanced stage and distant metastasis were the strongest predictors of both OS and DFS. In post hoc exploratory analyses, increasing SOD2 (HR 1.36 per point, p = 0.039) and HIF-1α scores (HR 1.80 per point, p = 0.022) showed nominal associations with worse OS; these findings are hypothesis-generating and should not be interpreted as evidence of independent prognostic value. Combined biomarker stratification showed a numerical stepwise pattern of OS curves, with the poorest survival observed in the both-high group, although statistical significance was not reached. High SOD2 expression is frequent in TNBC and may reflect underlying tumor biology; however, this was not independently confirmed in survival analyses. Continuous biomarker scoring suggests an incremental association with overall survival. Combined HIF-1α/SOD2 assessment did not demonstrate independent prognostic value in this cohort. These observations are hypothesis-generating and require validation in larger, prospectively designed cohorts before any clinical application can be considered.