Through analysis of preclinical models from endocrine receptor (ER) À/HER2þ and triple-negative (TN) inflammatory breast cancers (BCs) and of clinical BC samples, Villodre et al.(1) suggest that NDRG1 critically contributes to tumor growth and metastasis in aggressive ER-negative BCs. NDRG1 depletion reduces colony formation, migration, and invasion; number of tumor-initiating cells; and mTOR/AKT signaling in vitro and primary tumor growth and brain metastasis in vivo. NDRG1 expression is associated with aggressiveness features of clinical samples (ERÀ, TNBC, HER2þ, high grade, metastatic samples) and shorter overall survival in multivariate analysis, including pathological stage and ER status. Because previous literature describes NDRG1 as a metastasis suppressor in less aggressive ERþ BC cell lines, the authors suggest that “NDRG1 has a context-dependent function in BC.” In fact, the clinical relevance of NDRG1 expression in BC has never been assessed in series large enough to allow analysis by molecular subtype. To fill this gap, we retrospectively examined NDRG1 mRNA expression in 8982 primary BC samples pooled from 36 public datasets (Supplementary Table 1, available online)(2), including notably 5929 ERþ/HER2À and 1936 TN cases. The methods used are detailed in the Supplementary Methods (available online).

We confirmed the independent unfavorable prognostic value of high NDRG1 expression (cutoff ¼ median) for overall survival in the whole population in multivariate analysis, including pathological stage, but also, in contrast with Villodre et al.(1), other major prognostic variables such as pathological tumor grade, type, and molecular subtypes (hazard ratio [HR] ¼ 1.34, 95% confidence interval [CI] ¼ 1.13 to 1.60). In analysis per molecular subtype, we found independent poor-prognosis value in the aggressive TN subtype (HR ¼ 1.59, 95% CI ¼ 1.01 to 2.49) but also in the less aggressive ERþ/HER2À subtype (HR¼ 1.40, 95% CI ¼ 1.14 to 1.73; Figure 1, A and B; Supplementary Table 2, available