Abstract
E2F transcription factors are involved in cell cycle regulation and synthesis of DNA in mammalian cells, and simultaneously play important roles in the development and progression of cancer when dysregulated. E2F8, a novel identified E2F family member, was found to be associated with the progression of several human cancers; however, the biological role and clinical significance of E2F8 in breast cancer remain to be further elucidated. Herein, we report that E2F8 is robustly elevated in breast cancer cell lines and clinical breast cancer tissue samples, respectively. The high expression level of E2F8 significantly correlates with clinical progression (P = 0.001), poor patient survival (P < 0.001) and a high Ki67 staining index (P = 0.008) in 187 human breast cancer specimens. Furthermore, we find that overexpressing E2F8 promotes, whereas silencing E2F8 suppresses, the proliferation and tumorigenicity of breast cancer cells both in vitro and in vivo. We further demonstrate that E2F8 transcriptionally upregulates CCNE1 and CCNE2 via directly interacting with their respective gene promoter, which accelerates the transition of G1 to S phase of breast cancer cells. Taken together, these findings uncover a novel biologic role and regulatory mechanism of E2F8 responsible for the progression of breast cancer, indicating E2F8 may represent a novel prognostic biomarker and therapeutic target against breast cancer.
Highlights
Sustaining proliferation is thought to be the most fundamental hallmark of cancer [1]
We demonstrate that E2F8 can promote entry into the G1/S phase of the cell cycle via transcriptionally upregulating cyclin E1 and cyclin E2 expression, contributing to cell proliferation and tumorigenicity in human breast cancer
The mRNA and protein levels of E2F8 were differentially upregulated in all 8 freshly-frozen breast cancer samples as compared to the matched adjacent non-tumor tissues (Figure 1E and 1F), suggesting that E2F8 is upregulated in breast cancer cell lines and breast cancer tissues
Summary
Sustaining proliferation is thought to be the most fundamental hallmark of cancer [1]. The production and release of proliferative signals that instruct entry into cell cycle progression are dysregulated in cancer cells, thereby breaking homeostasis of cell number and causing uncontrolled cell proliferation. During the cell cycle progression, G1/S phase transition emerges as one of the most critical steps, which involves activation of cyclin-dependent kinases (CDKs) by forming cyclinsCDK complex, phosphorylation of retinoblastoma (Rb), and E2F-mediated gene transcription [2]. Cyclin E (including cyclin E1 and cyclin E2) binds to CDK2, which in turn phosphorylates Rb to promote G1/S phase progression. Dysregulation of cyclin E-CDK2 activity is involved in various types of cancers, including breast, gastric, kidney and lung cancer, contributing to uncontrolled cell proliferation [3,4,5,6,7]. More detailed knowledge of cell cycle transition mechanisms would be beneficial to understanding the initiation and progression of breast cancer, but may provide new clues for the development of novel therapeutic strategies
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