Sialyl Lewis(X/A) and Cytokeratin Crosstalk in Triple Negative Breast Cancer

SIMPLE SUMMARY: Triple-negative breast cancer (TNBC) is aggressive, highly metastatic, and associated with poor patient prognosis. Sialyl-Lewis X and A (sLe(X/A)) are sugars with important roles in cell signalling and metastasis. We aimed to describe the relevance of sLe(X/A) in TNBC patients and its association with other biomarkers. We identified that sLe(X/A) negatively correlated with cytokeratins, structural proteins present at the cell cytoskeleton, and are involved in cell attachment, by using patient tissues, cell lines, and datasets. Our data suggests that sLe(X/A) is decorating proteins such as integrin alpha 6, deregulating cell signalling responsible for hemidesmosome formation, impacting cell adhesion, and promoting metastatic behaviour. This work highlights sLe(X/A) as an important biomarker behind TNBC malignancy to target and treat this breast cancer type. ABSTRACT: Triple-negative breast cancer (TNBC) encompasses multiple entities and is generally highly aggressive and metastatic. We aimed to determine the clinical and biological relevance of Sialyl-Lewis X and A (sLe(X/A))—a fucosylated glycan involved in metastasis—in TNBC. Here, we studied tissues from 50 TNBC patients, transcripts from a TNBC dataset from The Cancer Genome Atlas (TCGA) database, and a primary breast cancer cell line. All 50 TNBC tissue samples analysed expressed sLe(X/A). Patients with high expression of sLe(X/A) had 3 years less disease-free survival than patients with lower expression. In tissue, sLe(X/A) negatively correlated with cytokeratins 5/6 (CK5/6, which was corroborated by the inverse correlation between fucosyltransferases and CK5/6 genes. Our observations were confirmed in vitro when inhibition of sLe(X/A) remarkably increased expression of CK5/6, followed by a decreased proliferation and invasion capacity. Among the reported glycoproteins bearing sLe(X/A) and based on the STRING tool, α6 integrin showed the highest interaction score with CK5/6. This is the first report on the sLe(X/A) expression in TNBC, highlighting its association with lower disease-free survival and its inverse crosstalk with CK5/6 with α6 integrin as a mediator. All in all, sLe(X/A) is critical for TNBC malignancy and a potential prognosis biomarker and therapeutic target.