The epithelial–mesenchymal transition (EMT) transcription factors ZEB1 and ZEB2 play critical roles in cancer progression and metastasis. CD105 (endoglin), a marker of neovascularization, has also been implicated in tumor aggressiveness. However, their combined prognostic and clinicopathological relevance in breast carcinoma remains underexplored.

We evaluated ZEB1, ZEB2, and CD105 expression in the epithelial compartment of the tumor and tumor stroma via immunohistochemistry in 258 invasive breast cancer cases. Correlations were assessed with clinicopathologic features including metastatic patterns and molecular subtypes, as well as with overall survival (OS) and progression-free survival (PFS).

High epithelial expression of ZEB1 and ZEB2 was significantly associated with adverse prognostic parameters, particularly the presence of distant metastases. Specifically, high epithelial ZEB1 correlated with bone and distant metastases, high histologic grade, and triple-negative status. Epithelial ZEB2 was linked to brain and liver metastases and the triple-negative subtype. In survival analysis, epithelial ZEB1 independently predicted both OS (p < 0.001) and PFS (p = 0.020). Epithelial ZEB2 independently predicted PFS (p = 0.026) but not OS, indicating an endpoint-specific prognostic role. CD105 lacked independent prognostic value but was associated with multifocal tumors and PR positivity.

Epithelial ZEB1 and ZEB2 overexpression strongly correlates with aggressive tumor behavior and specific metastatic patterns in invasive breast carcinoma, particularly the triple-negative phenotype and visceral metastases. Epithelial ZEB1 independently predicted both OS and PFS, while epithelial ZEB2 showed endpoint-specific independent prognostic significance for PFS. These findings support ZEB1 and ZEB2 as candidate biomarkers and therapeutic targets for metastasis prevention in breast cancer.