SDC2 and FN as cargo proteins in circulating extracellular vesicles in obese breast cancer patients with lymph node metastasis

Abstract

Abstract Lymph node metastasis (LNM) is a pivotal determinant of breast cancer (BC) patient prognosis and treatment efficacy. Cell surface heparan sulfate proteoglycans (HSPGs), namely, syndecan-1 (SDC1), SDC2, and SDC4, are involved in cancer progression, metastasis, and regulate extracellular vesicles (EVs) biogenesis, including the microvesicles (MVs). This study analyzed MV-enriched EVs isolated from blood plasma of BC patients with negative (n = 19) and positive (n = 20) LNM (nLNM and pLNM, respectively) using differential centrifugation. Western blot analysis revealed significantly elevated SDC2 levels in MV-enriched EVs from pLNM cases compared to nLNM. Additionally, fibronectin (FN), a SDC2-interacting protein identified through STRING analysis, was also upregulated in pLNM MV-enriched EVs. In contrast, qRT-PCR showed reduced SDC2 (P < 0.01) and FN (P < 0.05) mRNA levels in tumor tissues of pLNM patients compared to nLNM. ROC analysis highlighted the diagnostic value of SDC2 (AUC: 0.8376) and FN (AUC: 0.8803) mRNA in differentiating LNM status. Bioinformatics analyses further confirmed the association of SDC2 and FN expression with BC staging and prognosis. These findings underscore the potential of circulating MV-enriched EV-associated SDC2 and FN, along with their tumor tissue mRNA expression, as potential predictive biomarkers for LNM and chemotherapy response in chemotherapy-naïve obese BC patients.