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Oncotarget. 2017 Jul 25;8(30):48875-48888. doi: 10.18632/oncotarget.16511.

The tumor suppressor interferon regulatory factor 8 inhibits β-catenin signaling in breast cancers, but is frequently silenced by promoter methylation.

Luo X1,2, Xiong X1, Shao Q1, Xiang T1, Li L3, Yin X1,2, Li X1, Tao Q1,3, Ren G1,2.

Author information

1
Chongqing Key Laboratory of Molecular Oncology and Epigenetics, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
2
Department of Endocrine and Breast Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.
3
Cancer Epigenetics Laboratory, Department of Clinical Oncology, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer and Li Ka Shine Institute of Health Sciences, The Chinese University of Hong Kong and CUHK Shenzhen Research Institute, Shatin, Hong Kong.

Abstract

Interferon (IFN) regulatory factor 8 is encoded by a novel candidate tumor suppressor gene (IRF8), its promotor is frequently methylated in multiple cancers. However, the promoter methylation status, functions and underlying mechanisms of IRF8 in breast cancer remain unclear. We found that IRF8 was downregulated in breast cancer cell lines and primary tumors, compared with normal breast tissues, mainly because of aberrant promoter methylation. However, its expression was not associated with pathological characteristics. Restoration of IRF8 expression suppressed cell proliferation, colony formation, 5-ethynyl-2'-deoxyuridine incorporation, cell migration and invasion, and induced apoptosis and cell cycle arrest in vitro. IRF8 also inhibited xenograft growth in nude mice in vivo. Competition with IRF8 function by IRF8 mutant (K79E) enhanced cell migration and invasion in 4T1 murine cells in vitro. Importantly, IRF8, as both downstream target gene and regulator of IFN-γ/STAT1 signaling, inhibited canonical β-catenin signaling. These findings identify IRF8 as a novel tumor suppressor regulating IFN-γ/STAT1 signaling and β-catenin signaling in breast cancer.

KEYWORDS:

breast cancer; interferon regulatory factor 8; methylation; tumor suppressor; β-catenin

PMID:
28388578
PMCID:
PMC5564732
DOI:
10.18632/oncotarget.16511
[Indexed for MEDLINE]
Free PMC Article

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