MUCL1 in triple-negative breast cancer: a novel marker associated with the luminal androgen receptor subtype

Abstract Triple-negative breast cancer (TNBC) comprises several molecularly distinct subtypes. The luminal androgen receptor (LAR) subtype is characterized by AR expression, displays luminal-like gene signatures, and often co-expresses FOXA1 and GCDFP-15, but its immunohistochemical identification remains challenging. Through transcriptomic analyses of GEO datasets, we identified MUCL1 as a candidate marker and validated its protein expression in a retrospective cohort of 106 TNBCs. MUCL1 was expressed in 25% of cases in our cohort, enriched in apocrine and lobular carcinomas, and strongly correlated with AR, FOXA1, and GCDFP-15. MUCL1-positive tumors occurred in older patients, were larger, and showed lower grade and proliferation, features which are known to be associated with the LAR subtype. Importantly, MUCL1–/AR+ tumors resembled MUCL1–/AR– rather than MUCL1-positive cases, suggesting that AR expression alone may not fully capture the underlying biology of this subgroup, while MUCL1 expression was associated with a more coherent clinicopathological phenotype aligned with LAR-associated features. Transcriptomic enrichment of hormone response and metabolic pathways in MUCL1-high tumors supports this association. Evidence linking both LAR and MUCL1 to reduced chemotherapy sensitivity highlights the clinical relevance of MUCL1.