Description

Methylation and silencing of irf8 expression correlates with the metastatic phenotype in breast cancer

Gatti, Gerardo¹; Roselli, Emiliano²; Araya, Paula²; Caballier, Maria E.³; Cordero, Vanesa³; Di Tada, Cecilia¹; Grupe, Veronica¹; Maccioni, Mariana²

(1) Fundación para el Progreso de la Medicina, Córdoba, Argentina. (2) CIBICI-CONICET, Facultad Ciencias Químicas. Universidad Nacional de Córdoba, Córdoba, Argentina.

(3) Hospital Nacional de Clínicas, Facultad de Medicina, Universidad Nacional de Córdoba, Córdoba, Argentina

The transcription factor interferon regulatory factor-8 (IRF8) is crucial for myeloid cell development and immune response and also acts as a tumor suppressor gene. Tumors silence the expression of IRF8, and disruption of its function leads to acquiring resistance to apoptosis, decreasing the activation of antitumor immune response and increasing the incidence of metastasis, however there is little information about IRF8 expression in breast cancer. The main goal of this work was to evaluate whether loss of IRF8 expression in breast cancer is an important factor in disease progression and metastasis. IRF8 expression was assessed by immunohistochemistry in breast ductal carcinoma and sentinel nodes samples. To evaluate whether silencing of IRF8 expression correlates with epigenetic changes, we performed Metylation-specific PCR. IRF8 is expressed in normal breast tissue and breast tumor samples of different tumor histological grades, although with less intensity in tumors with histological grade III. In contrast, expression of IRF8 was not detected in metastatic foci in sentinel nodes. Furthermore, expression of IRF8 was not evidenced in human tumor cell lines. DNA methylation assays showed that the promoter region of IRF8 was methylated in breast tumor cell lines, suggesting a mechanism responsible for the silencing of IRF8 in breast cancer samples. In conclusion, our results indicate that the expression of IRF8 correlates inversely with the metastatic phenotype in breast cancer, and that transcriptional silencing of IRF8 in breast tumor cells correlates with epigenetic changes. These results suggest that IRF8 may have clinical value as potential prognostic marker in breast cancer.