CCCTC-binding factor inhibits breast cancer cell proliferation and metastasis via inactivation of the nuclear factor-kappaB pathway.

Jie Wu,Ling Qiu,Peng-Chang Li,Jian-Hua Han,Xue-Min Xie,Xiu-Zhi Guo,Jun-Yi Pang,Jia-Yao Li,Guo-You Liu,Yi-Cong Yin

doi:10.18632/oncotarget.18977

Abstract

CCCTC-binding factor (CTCF) is an important epigenetic regulator implicated in multiple cellular processes, including growth, proliferation, differentiation, and apoptosis. Although CTCF deletion or mutation has been associated with human breast cancer, the role of CTCF in breast cancer is questionable. We investigated the biological functions of CTCF in breast cancer and the underlying mechanism. The results showed that CTCF expression in human breast cancer cells and tissues was significantly lower than that in normal breast cells and tissues. In addition, CTCF expression correlated significantly with cancer stage (P = 0.043) and pathological differentiation (P = 0.029). Furthermore, CTCF overexpression resulted in the inhibition of proliferation, migration, and invasion, while CTCF knockdown induced these processes in breast cancer cells. Transcriptome analysis and further experimental confirmation in MDA-MD-231 cells revealed that forced overexpression of CTCF might attenuate the DNA-binding ability of nuclear factor-kappaB (NF-κB) p65 subunit and inhibit activation of NF-κB and its target pro-oncogenes (tumor necrosis factor alpha-induced protein 3 [TNFAIP3]) and genes for growth-related proteins (early growth response protein 1 [EGR1] and growth arrest and DNA-damage-inducible alpha [GADD45a]). The present study provides a new insight into the tumor suppressor roles of CTCF in breast cancer development and suggests that the CTCF/NF-κB pathway is a potential target for breast cancer therapy.

Highlights

Breast cancer continues to be the most common malignant tumor in women worldwide, with an estimated 25% of new cancer cases diagnosed [1,2,3,4]
The expression of CTCF was analyzed in only three breast cancer cell lines; further analysis was carried out to verify the difference in CTCF expression using normal and tumor breast tissues
These results suggested that CTCF expression is downregulated in breast cancer tissues and cell lines

Summary

Introduction

Breast cancer continues to be the most common malignant tumor in women worldwide, with an estimated 25% of new cancer cases diagnosed [1,2,3,4]. Nuclear factor-kappa B (NF-kB), the key transcription factor that mediates the inflammatory response, is involved in carcinogenesis-associated cellular processes, such as inflammation, proliferation, invasion, metastasis, angiogenesis, differentiation, and survival [5, 6]. Studies have shown that NF-kB regulates the expression of several responsive genes that are associated closely with tumorigenesis, such as those encoding www.impactjournals.com/oncotarget cytokines, transcription factors, growth factors, and apoptosis regulators [7]. Aberrant activation of NF-κB occurs in most cancers, including breast cancer [8,9,10]. Many negative regulators, including microRNAs, long non-coding RNAs, and regulatory proteins, function as tumor suppressors by inhibiting the uncontrolled activation of NF-kB [5, 6, 11]

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Results

Conclusion