Restoration of GATA4 expression impedes breast cancer progression by transcriptional repression of ReLA and inhibition of NF-κB signaling.

Abstract

There are increasing reports of aberrant expression of GATA4, correlated with oncogenesis and malignant progression in some solid tumors, but whether GATA4 functions as an oncogenic driver or a tumor suppressor in carcinogenesis remains controversial. Because the role and mechanism of GATA4 in breast cancer (BrCa) remain poorly understood, we focused on the expression of GATA4 in BrCa cell lines and tissues and its mechanism in breast oncogenesis. Semiquantitative real-timepolymerase chain reaction (RT-PCR), quantitative RT-PCR, Western blot analysis, and immunohistochemistry were used to detect expression of GATA4 in BrCa cell lines and adjacent breast tissues. Methylation statuses of the GATA4 promoter were studied using methylation-specific PCR in BrCa cell lines.The effects of GATA4 on proliferation, invasion, and cell cycle were also analyzed. Compared with adjacent breast tissue, GATA4 expression in BrCa tissue and cell lines was obviously lower and low expression levels of GATA4 predicted poor outcome. Methylation of GATA4 occurred in almost all of BrCa cell lines . GATA4 overexpression decreased viability, invasion, migration, and epithelial-to-mesenchymal transition of MB-231 and BT549 cells, and markedly induced cell cycle arrest and apoptosis. Exogenous expression GATA4 accompanied a significant alteration of MMP2, MMP3, E-cadherin, and N-cadherin expression and induction of the caspase-8 pathway. Moreover, GATA4 could directly repress RelA (p65) transcription, reduce the nuclear phosphorylation-p65 and upregulate inhibitor kappa B expression. Altogether, GATA4 plays a tumor-suppressive role via repression of NF-κB signaling in BrCa cells. Our findings suggest that GATA4 is a potential prognostic biomarker and gene therapeutic target for human BrCa.