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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

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Jandrey, Elisa H. F. [1] ; Moura, Ricardo P. [2] ; Andrade, Luciana N. S. [3] ; Machado, Camila L. [3] ; Campesato, Luiz Felipe [1] ; Leite, Katia Ramos M. [4] ; Inoue, Lilian T. [1] ; Asprino, Paula F. [1] ; da Silva, Ana Paula M. [2] ; de Barros, Alfredo Carlos S. D. [5] ; Carvalho, Andre [6] ; de Lima, Vladmir C. [7] ; Carraro, Dirce M. [7] ; Brentani, Helena P. [8] ; da Cunha, Isabela W. [9] ; Soares, Fernando A. [9] ; Parmigiani, Raphael B. [2] ; Chammas, Roger [3] ; Camargo, Anamaria A. [2, 1] ; Costa, Erico T. [2, 1]
Total Authors: 20
Affiliation:
[1] Hosp Siriolibanes, Ctr Oncol Mol, Sao Paulo, SP - Brazil
[2] LICR, Sao Paulo - Brazil
[3] Inst Canc Estado Sao Paulo, Ctr Invest Translac Oncol, Lab Oncol Expt, Sao Paulo, SP - Brazil
[4] Hosp Siriolibanes, Lab Patol, Sao Paulo, SP - Brazil
[5] Hosp Siriolibanes, Dept Mastol, Sao Paulo, SP - Brazil
[6] Hosp Canc Barretos, Barretos, SP - Brazil
[7] Fundacao Antonio Prudente, AC Camargo Canc Ctr, Ctr Int Pesquisa, Sao Paulo, SP - Brazil
[8] Univ Sao Paulo, Fac Med, Inst Psiquiatria, LIM23, Sao Paulo - Brazil
[9] Hosp Sao Luis, Rede DOR, Sao Paulo, SP - Brazil
Total Affiliations: 9
Document type: Journal article
Source: NPJ BREAST CANCER; v. 5, APR 5 2019.
Web of Science Citations: 0
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 beta 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. (AU)