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NDRG4 promoter hypermethylation is a mechanistic biomarker associated with metastatic progression in breast cancer patients.

ABSTRACT: The risk of developing metastatic disease in breast cancer patients is traditionally predictable based on the number of positive axillary lymph nodes, complemented with additional clinicopathological factors. However, since lymph node-negative patients have a 20-30% probability of developing metastatic disease, lymph node information alone is insufficient to accurately assess individual risk. Molecular approaches, such as multigene expression panels, analyze a set of cancer-related genes that more accurately predict the early risk of metastasis and the treatment response. Here, we present N-Myc downstream-regulated gene 4 (NDRG4) epigenetic silencing as a mechanistic biomarker of metastasis in ductal invasive breast tumors. While aberrant NDRG4 DNA hypermethylation is significantly associated with the development of metastatic disease, downregulation of NDRG4 transcription and protein expression is functionally associated with enhanced lymph node adhesion and cell mobility. Here, we show that epigenetic silencing of NDRG4 modulates integrin signaling by assembling ?1-integrins into large punctate clusters at the leading edge of tumor cells to promote an "adhesive switch," decreasing cell adhesion to fibronectin and increasing cell adhesion and migration towards vitronectin, an important component of human lymph nodes. Taken together, our functional and clinical observations suggest that NDRG4 is a potential mechanistic biomarker in breast cancer that is functionally associated with metastatic disease.

SUBMITTER: Jandrey EHF

PROVIDER: S-EPMC6450950 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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NDRG4 promoter hypermethylation is a mechanistic biomarker associated with metastatic progression in breast cancer patients.

Jandrey Elisa H F EHF Moura Ricardo P RP Andrade Luciana N S LNS Machado Camila L CL Campesato Luiz Felipe LF Leite Katia Ramos M KRM Inoue Lilian T LT Asprino Paula F PF da Silva Ana Paula M APM de Barros Alfredo Carlos S D ACSD Carvalho Andre A de Lima Vladmir C VC Carraro Dirce M DM Brentani Helena P HP da Cunha Isabela W IW Soares Fernando A FA Parmigiani Raphael B RB Chammas Roger R Camargo Anamaria A AA Costa Érico T ÉT

NPJ breast cancer 20190405

The risk of developing metastatic disease in breast cancer patients is traditionally predictable based on the number of positive axillary lymph nodes, complemented with additional clinicopathological factors. However, since lymph node-negative patients have a 20-30% probability of developing metastatic disease, lymph node information alone is insufficient to accurately assess individual risk. Molecular approaches, such as multigene expression panels, analyze a set of cancer-related genes that mo ...[more]

PMID: 30963110

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Project description:PURPOSE:This study evaluates the prognostic significance of MST1R (RON) expression in breast cancer with respect to disease progression, long-term survival, subtype, and association with conventional prognostic factors. METHODS:The approach includes interrogation of survival and tumor staging with paired MST1R RNA expression from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets. Protein expression evaluation was performed using immunohistochemistry (IHC) staining of MST1R on breast cancer tissue samples from the Cancer Diagnosis Program Breast Cancer Progression tissue microarray and locally obtained breast tumor tissue samples analyzed with paired survival, metastasis, and subtype. RESULTS:Data from TCGA (n?=?774) show poorer relapse-free survival (RFS) in patients with high MST1R expression (P?=?0.32) and no difference in MST1R expression based on tumor stage (P?=?0.77) or nodal status (P?=?0.94). Patients in the GEO-derived Kaplan-Meier Plotter microarray dataset demonstrate the association of MST1R and poorer overall survival (n?=?1402, P?=?0.018) and RFS in patients receiving chemotherapy (n?=?798, P?=?0.041). Patients with high MST1R expression display worse overall survival (P?=?0.01) and receiver operator characteristic (ROC) analysis demonstrate the predictive capacity of increased MST1R with early death (P?=?0.0017) in IHC-stained samples. Paired IHC-stained breast tumor samples from the primary versus metastatic site show MST1R expression is associated with metastatic progression (P?=?0.032), and ROC analysis supports the predictive capacity of MST1R in metastatic progression (P?=?0.031). No associations of MST1R with estrogen receptor (ER), progesterone receptor (PR), both ER and PR, HER2 positivity, or triple-negativity were found (P?=?0.386, P?=?0.766, P?=?0.746, P?=?0.457, P?=?0.947, respectively). CONCLUSIONS:MST1R expression has prognostic value in breast cancer with respect to survival and metastatic progression. MST1R expression is not associated with tumor stage, nodal status, or subtype.

Project description:BackgroundAberrant DNA methylation plays a crucial role in the progression of myeloid neoplasms. Previously, our literature reported that slit guidance ligand 2 (SLIT2) promoter methylation was associated with disease progression and indicated a poor prognosis in patients with myelodysplastic syndrome. Herein, we further investigated the clinical implications and role of SLIT2 promoter methylation in patients with chronic myeloid leukemia (CML).MethodsThe level of SLIT2 promoter methylation was determined in 104 CML patients, and its clinical significance was analyzed. Moreover, demethylation studies were performed in K562 cells to determine the epigenetic mechanism by which SLIT2 promoter methylation is regulated in CML.ResultsThe level of SLIT2 promoter methylation was similar between CML patients and controls. However, deeper analysis revealed that the SLIT2 promoter methylation level in the accelerated phase (AP) and blast crisis (BC) was markedly higher than that in the chronic phase (CP) and controls. Additionally, a marked difference was identified between the SLIT2 promoter hypermethylated and non-hypermethylated groups among CML patients grouped by clinical stage. The frequency of SLIT2 hypermethylation was markedly increased with the progression of clinical stage, that is, it was the lowest in CP samples (12/80, 15%), higher in AP samples (4/8, 50%) and the highest in BC samples (11/16, 69%). Importantly, the level/density of SLIT2 promoter methylation was significantly higher in the advanced stage than in the early stage among the 6 tested paired CML patients. Epigenetically, the expression of the SLIT2-embedded non-coding genes SLIT2-IT1 and miR-218 expression was decreased in patients with CML. SLIT2 promoter hypermethylated cases had a markedly lower SLIT2-IT1 expression level than SLIT2 promoter non-hypermethylated cases. Moreover, SLIT2-IT1 and miR-218 expression was remarkably upregulated in a dose-dependent manner after demethylation treatment of K562 cells.ConclusionsHypermethylation of the SLIT2 promoter is correlated with disease progression in CML. Furthermore, SLIT2 promoter methylation may function by regulating the expression of the SLIT2-embedded non-coding genes SLIT2-IT1 and miR-218 during CML progression.

Dataset Information

NDRG4 promoter hypermethylation is a mechanistic biomarker associated with metastatic progression in breast cancer patients.

Publications

NDRG4 promoter hypermethylation is a mechanistic biomarker associated with metastatic progression in breast cancer patients.

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