NDRG1 in Aggressive Breast Cancer Progression and Brain Metastasis

Abstract

Background N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies including breast cancer yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive. Methods To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7–10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test was used to analyze the associations between NDRG1 and time-to-event outcomes. A multivariate Cox regression model was used to determine independent prognostic factors. All statistical tests were 2-sided. Results We generated new sublines that exhibit a distinct propensity to metastasize to the brain. NDRG1-high expressing cells produced more prevalent brain metastases (100% vs 44.4% for NDRG1-low sublines, P = .01, Fisher’s exact test), greater tumor burden, and reduced survival in mice. In aggressive breast cancer cell lines, silencing NDRG1 led to reduced migration, invasion, and tumor-initiating cell subpopulations. In xenograft models, depleting NDRG1 inhibited primary tumor growth and brain metastasis. In patient breast tumors, NDRG1 was associated with aggressiveness: NDRG1-high expression was also associated with shorter overall survival (hazard ratio [HR] = 2.27, 95% confidence interval [CI] = 1.20 to 4.29, P = .009) and breast cancer-specific survival (HR = 2.19, 95% CI = 1.07 to 4.48, P = .03). Multivariable analysis showed NDRG1 to be an independent predictor of overall survival (HR = 2.17; 95% CI = 1.10 to 4.30; P = .03) and breast cancer-specific survival rates (HR = 2.27; 95% CI = 1.05 to 4.92; P = .04). Conclusions We demonstrated that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers and that NDRG1-high expression correlates with worse clinical outcomes, suggesting that NDRG1 may serve as a therapeutic target and prognostic biomarker in aggressive breast cancers.

TGFβ Governs the Pleiotropic Activity of NDRG1 in Triple-Negative Breast Cancer Progression

“…On the contrary, the cytoplasmic p-NDRG1 score threshold was set at 12.5, with no association with patient survival (Table S1). Taken together, these results confirmed that p-NDRG1 expression is predominantly cytoplasmic, as reported by others [9,11,26]. Notably, we herein showed for the first time that loss of p-NDRG1 nuclear expression can be a common event in TNBC that could negatively affect patient survival.…”

“…Subcellular localization of NDRG1 exemplifies its cancer-type-dependent pleiotropy, for instance, nuclear NDRG1 protein expression is associated with poor prognosis in colorectal cancer [12] and favorable prognosis in renal carcinoma [13]. This duality was also seen in breast cancer, with NDRG1 being reported as a metastasis suppressor and tumor promoter in estrogen-receptor (ER) positive and negative breast cancers, respectively [9,[14][15][16][17][18]. In TNBC, NDRG1 expression was found to correlate with poorer patient survival, however, inconsistent experimental results across the studies within the same tumor subtype indicate not only a cell-dependent pleiotropy but also that the underlying mechanisms that trigger NDRG1 pleiotropy are still unknown [9,17,18].…”

“…International Publisher or pancreatic cancer [3][4][5], but it showed a pro-oncogenic role in other cancers, including aggressive breast cancer, by promoting tumor growth, metastasis, angiogenesis and poor prognosis [6][7][8][9]. Multiple phosphorylation sites have been described for this protein, and the relationship between post-translational modifications, function, regulation, and subcellular localization of NDRG1 has been established.…”

“…The dual role of NDRG1 as a metastasis/tumor progressor or suppressor has been reported in breast cancer [9,[14][15][16][17][18]. Inconsistent and variable results in TNBC cell lines have been reported when assessing the role of NDRG1 on proliferation, metastatic abilities, and tumor-initiating cells in TNBC cell lines [9,17,18].…”

Elucidating the pharmacological mechanism by which Si-Wu-Tang induces cellular senescence in breast cancer via multilevel data integration

“…Consistent with previous reports, NDRG1 was found to be a risk factor for BC. NDRG1 has been shown to drive tumor progression and brain metastasis in aggressive breast cancer [ 41 ]. ERRFI1 is a tumor suppressor in tumor cells in situ , and its expression is required to prevent apoptosis and BC cell metastasis [ 42 ].…”