NDRG1 expression is an independent prognostic factor in inflammatory breast cancer

Abstract

NDRG1 is widely described as a metastasis suppressor in breast cancer. However, we found that NDRG1 is critical in promoting tumorigenesis and brain metastasis in mouse models of inflammatory breast cancer (IBC), a rare but highly aggressive form of breast cancer. We hypothesized that NDRG1 is a prognostic marker associated with poor outcome in patients with IBC. Microarray gene expression data from the IBC Consortium dataset were analyzed to compare NDRG1 expression between IBC and non-IBC tumors and among breast cancer subtypes. NDRG1 levels in tissue microarrays from 64 IBC patients were evaluated by immunohistochemical staining with anti-NDRG1 primary antibody (32 NDRG1-low [[≤] median], 32 NDRG1-high [>median]). Overall and disease-free survival (OS and DSS) were analyzed with Kaplan-Meier curves and log-rank test. NDRG1 mRNA expression was higher in IBC than in non-IBC tumors (p=0.007), and in more aggressive HER2+ and basal-like vs luminal IBC subtypes (p<0.0001). Univariate analysis showed NDRG1 expression, tumor grade, disease stage, estrogen receptor (ER) status, and receipt of adjuvant radiation to be associated with OS and DSS. NDRG1-high patients had poorer 10-year OS and DSS than NDRG1-low patients (OS, 19% vs 45%, p=0.0278; DSS, 22% vs 52%, p=0.0139). On multivariable analysis, NDRG1 independently predicted OS (hazard ratio [HR]=2.034, p=0.0274) and DSS (HR=2.287, p=0.0174). NDRG1-high ER-negative tumors had worse outcomes OS, p=0.0003; DSS, p=0.0003; and NDRG1-high tumors that received adjuvant radiation treatment had poor outcomes (OS, p=0.0088; DSS, p=0.0093). NDRG1 correlated positively with aggressive tumor characteristics in IBC and was a significant independent prognostic factor for DSS and OSS in IBC patients. Targeting NDRG1 may represent a novel strategy for improving clinical outcomes for patients with IBC.