GALNT6 localization is associated with gland-forming architecture and morphological differentiation in luminal A breast cancer.

Altered protein glycosylation is a hallmark of cancer and has been implicated in the regulation of tumor cell behavior and tissue organization. N-Acetylgalactosaminyltransferase 6 (GALNT6), an initiating enzyme of mucin-type O-glycosylation, has been associated with breast cancer progression. However, whether GALNT6 exhibits subtype-specific expression and distinct histopathological localization patterns in breast cancer tissues has remained unclear. In this study, we performed subtype-stratified analyses of TCGA-BRCA RNA-seq data. We identified preferential GALNT6 upregulation in luminal A breast cancer, whereas expression was low in basal-like tumors and normal breast tissue. Gene co-expression network analysis further demonstrated that GALNT6-associated modules in luminal A breast cancer were enriched for estrogen receptor (ER) signaling, mammary epithelial development, and apical membrane-associated pathways, indicating close association with luminal epithelial transcriptional programs. To further characterize GALNT6 localization patterns in clinical tissues, we performed region-based histopathological and immunofluorescence analyses of luminal A breast cancer specimens. These analyses revealed architecture-dependent subcellular localization of GALNT6 associated with distinct Golgi organization patterns, showing apical/luminal-biased distribution in gland-forming regions and less polarized and more broadly distributed cytoplasmic localization in non-gland-forming tumor regions. E-cadherin was enriched at basolateral intercellular junctions, particularly in GALNT6-high tumors. Together, these findings identify GALNT6 as a luminal A-associated glycosylation-related marker linked to luminal epithelial transcriptional programs and architecture-dependent subcellular localization patterns in breast cancer.