Abstract
Simple SummaryInflammatory breast cancer (IBC) is a rare and aggressive variant of breast cancer that is responsible for a significant number of breast cancer-related deaths. Herein, we describe how the expression of a specific protein named N-myc downstream-regulated gene 1 (NDRG1), commonly described as a gene that prevents the spread of cancer cells to distant organs, may have a paradoxical role in cancer progression in IBC. We found that the level of expression of NDRG1 in tumor tissues predicts the survival outcome of patients with IBC. We also observed that NDRG1, together with other important prognostic factors such as estrogen receptor status and stage, could be used to further analyze prognostic outcome or treatment response of patients.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. NDRG1 levels in tissue microarrays from 64 IBC patients were evaluated by immunohistochemical staining with NDRG1 (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. 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 was a significant independent prognostic factor for OS and DSS in IBC patients. Targeting NDRG1 may represent a novel strategy for improving clinical outcomes for patients with IBC.
Highlights
Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer
Our findings showed that high expression of N-myc downstream-regulated gene 1 (NDRG1) in IBC tumors was an independent predictor of worse OS and disease-specific survival (DSS)
To determine whether NDRG1 protein expression is associated with outcome in IBC, immunohistochemical staining was performed on tissue microarray (TMA) from 64 patients with primary IBC who were treated between 1991 and 2004 at The University of Texas MD Anderson Cancer Center
Summary
Inflammatory breast cancer (IBC) is one of the most aggressive forms of breast cancer. Even with multimodality treatment approaches that include systemic chemotherapy, surgery, and radiation therapy, the prognosis for patients with IBC is worse than for non-IBC patients (overall survival (OS) rates 40% versus 63% at 5 years) [5,6,7]. This may be due in part to 70% of IBC patients presenting with aggressive subtypes of HER2+ or triple-negative breast cancer (TNBC), compared with 40% of non-IBC tumors [8]. Efforts have been undertaken to identify molecular markers and therapeutic targets distinct to IBC and have identified important targets and pathways, including
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