Role of SALL4 and Nodal in the prognosis and tamoxifen resistance of estrogen receptor-positive breast cancer.

Abstract

Despite the discovery of a number of different mechanisms underlying tamoxifen resistance, its molecular pathway is not completely clear. The upregulation of SALL4 and Nodal has been reported in breast cancer. Nevertheless, their role in tamoxifen resistance has not been investigated. In the present study, we compared Nodal and SALL4 expression in 72 tamoxifen sensitive (TAMS) and tamoxifen-resistant (TAMR) patients. Afterward, the correlation of expression data with clinicopathological features and survival of patients was studied. Results showed that both SALL4 and Nodal were significantly upregulated in TAMR compared to TAMS patients. Besides, there was a positive association between Nodal and SALL4 expression. Furthermore, we evaluated their correlation with the expression of Oct4, Nanog and Sox2 stemness markers. The results demonstrated that in most tissue samples there was a positive correlation between Nodal and SALL4 expression with these stemness markers. Besides, the overexpression of SALL4 and Nodal significantly correlated with the N stage. Moreover, the overexpression of SALL4 was associated with extracapsular invasion and lymphatic invasion. High level expressions of SALL4 and Nodal had a significant association with worse disease-free survival (DFS) rates. In addition, increased level of Nodal expression provides a superior predictor factor for DFS. The multivariate Cox regression analysis also revealed that for DFS, perineural invasion (PNI) was independently an unfavorable prognostic value. These findings suggest that the high expression of SALL4 and Nodal could contribute to tamoxifen resistance and worse survival rates in tamoxifen-treated ER⁺ breast cancer patients.