Expression and clinical significance of carcinoembryonic antigen-related cell adhesion molecule 6 in breast cancers

Abstract

Carcino-embryonic antigen-related cell adhesion molecule 6 (CEACAM6), one of the members of human carcino-embryonic antigens, is a multifunctional regulatory protein involved in various cellular processes in cancers. Its role in malignant transformation and the clinical significance has been extensively studied in colonic and pancreatic cancers. However, relatively few studies have been done on breast cancers. In the current study, CEACAM6 expression in two independent cohorts of invasive breast cancers were evaluated immunohistochemically and correlated with clinico-pathological features, biomarker profiles and patient survival. In the primary cohort, CEACAM6 expression was detected in 37.1% (312/840) of primary invasive cancers. It was positively correlated with HER2 (p<0.001). Concordantly, HER2-OE subtype showed the highest CEACAM6 expression (62.7%) among all molecular subtypes; whereas, other subtypes also showed substantial CEACAM6 expression (21.8-37.5%). Interestingly, a significantly worse overall survival was found in high pN stage HER2 positive cancers with CEACAM6 positivity (log-rank=4.452, p=0.035) and this could be validated in an independent cohort. Additionally, HER2 signaling was found to induce SMAD3 phosphorylation and CEACAM6 expression in a cell line model. Likewise, in the primary tumors, a positive association was found between HER2 and SMAD3 phosphorylation in CEACAM6 positive cancers (p=0.012). Overall, CEACAM6 was widely expressed in different molecular subtypes, but highest and significantly in HER2-OE breast cancer. Within this group, CEACAM6 was associated with adverse high nodal stage patient outcome. Given the wide expression of CEACAM6 in all breast cancers, its roles as prognostic marker and therapeutic target warrant further evaluation.