Abstract
BACKGROUND: The use of established prognostic markers has improved the diagnostic stratification and therapeutic approaches of breast cancer. Ubiquitin-like modifier activating enzyme 1 (UBA1), a key enzyme in the ubiquitin-proteasome pathway, has been reported to play a role in the pathogenesis of various malignant tumors. However, its functional impact on breast cancer progression, especially across intrinsic subtypes, remains poorly understood. This study aimed to evaluate the prognostic relevance of UBA1 protein expression in patients with breast cancer. METHODS: Formalin-fixed, paraffin-embedded (FFPE) tissue samples from 413 chemotherapy-naïve patients with invasive breast cancer were obtained from the Institute of Surgical Pathology (ISP) at the University Medical Centre Freiburg in Germany. Haematoxylin and eosin (H&E)-stained slides were digitised and annotated to define regions of interest (ROIs) for tissue microarray (TMA) construction. TMA sections were immunohistochemically stained for UBA1 expression and intrinsic subtype markers, including oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), and Ki-67. All slides were digitised. UBA1 and intrinsic markers were evaluated and analysed using AI-assisted image analysis software (HALO AI). Furthermore, UBA1 expression was analysed separately in both tumor cells and tumor-associated stroma. All results were statistically correlated with clinicopathological data parameters. RESULTS: High UBA1 expression in both the tumor and stromal compartments was significantly associated with reduced overall survival (OS). Subtype-specific analyses revealed that elevated stromal UBA1 expression, particularly in the cytoplasm, was associated with poorer survival in luminal A and luminal B subtypes. Conversely, increased nuclear UBA1 expression in tumor cells was associated with worse outcomes in the luminal B subtype. Multivariable Cox regression analyses revealed that UBA1 expression in tumor cells was an independent prognostic marker. Furthermore, bivariate analyses revealed that high stromal UBA1 expression was associated with a broader range of adverse clinicopathological parameters, most notably at the cytoplasmic level. CONCLUSION: This study highlights the prognostic significance of UBA1 protein expression in breast cancer, thereby demonstrating its potential utility as a diagnostic and therapeutic target.