Beyond Sulfation: Integrated Immunohistochemical, Genomic, and Proteomic Profiling Identifies PAPSS1 as a Potential Regulator of Breast Cancer Progression

Background: PAPSS1 (3′-Phosphoadenosine 5′-Phosphosulfate Synthase 1) plays a central role in the sulfation process that regulates estrogen activity; however, its pattern of expression and association with clinicopathological features in breast carcinoma (BC) are not fully examined. Methods: A total of 150 BC specimens with clinicopathological and 10-year follow-up data were analyzed. PAPSS1 protein expression was assessed using immunohistochemistry (IHC) and correlated with clinicopathological parameters and patient outcome. Transcriptomic and promotor methylation analyses were performed using TCGA-BRCA through UALCAN. Proteomic data was evaluated using the CPTAC dataset, and the gene interaction network was analyzed using STRING. Results: IHC demonstrated significantly higher PAPSS1 expression in invasive carcinomas compared with non-invasive carcinoma and with normal mammary acini (p < 0.0001). High expression was associated with the presence of vascular invasion (VI) (p = 0.003), LN metastasis (p = 0.008), and higher PAPSS1 expression in tumor capillaries (p < 0.001). CPTAC analyses confirmed significantly elevated PAPSS1 in tumors versus normal tissues (p < 0.0001), particularly in stage II and III tumors, triple-negative BC, and basal stromal-related molecular subtypes. The transcriptomic data showed different expression patterns according to tissue type; it is higher in GIT tumors. The opposite was found in lung and pancreatic carcinoma. In BC, transcriptional expression was not different between normal and tumors; it was lower in higher nodal stages and highest in medullary carcinoma and in TP53-mutant tumors. Conclusions: PAPSS1 is overexpressed in BC and is associated with VI, LN metastasis, and tumor progression, suggesting a potential role in BC aggressiveness. Further studies are recommended to explore its mechanistic role.