br E F is found highly expressed in several

E2F5 is found highly expressed in several tumors, such as glioblas-toma,40 and prostate cancer.41 Downregulation of E2F5 was also 
found in MCF7 cells, and it significantly inhibited cell proliferation, migration, and invasion and increased cell-cycle arrest at the G0/G1 stage in vitro.23 Moreover, Cai et al.24 discovered that E2F5 exhibited higher levels in four breast cancer cell lines and 12 tissue samples and functioned as an oncogene in breast cancer. In this report, we demonstrated that the LY 379268 of E2F5 in breast cancer tissues was higher than that in normal tissues, but this expression was not markedly correlated with tumor stage in patients with breast can-cer. A higher E2F5 expression was significantly correlated with poor OS, FP, PPS, and DMFS in all of the patients with breast cancer.
E2F6 is reported negatively regulated BRCA1,25 methylation of whose promoter has been reported to occur sporadically in breast cancer, with proportions ranging from 11% to 31%.26 However, the prognostic role of E2F6 in breast cancer has yet to be investigated. In this report, we demonstrated that the expression of E2F6 in breast cancer tissues was lower than that in normal tissues, but this expression was not correlated with tumor stage in patients with breast cancer. A lower E2F6 expression was correlated with poor OS, FP, PPS, and DMFS in all of the patients with breast cancer, but with no significance.
E2F7 and E2F8 function as transcriptional repressors.42 They also likely serve as activators. E2F7 expression was significantly elevated in ER-positive breast cancer compared with normal breast tissues, and E2F7 overexpression conferred resistance to tamoxifen in
www.moleculartherapy.org
Figure 7. The Functions of E2Fs and Genes Significantly Associated with E2F Alterations
The functions of E2Fs and genes significantly associated with E2F alterations were predicted by the analysis of gene ontology (GO) by DAVID (Database for Annotation, Visualization and Integrated Discovery) tools (https://david.ncifcrf.gov/summary.jsp). GO enrichment analysis predicted the functional roles of target host genes based on three aspects, including (A) biological processes, (B) cellular components, and (C) molecular functions.
MCF7 cells.27 Upregulation of E2F8 promotes cell proliferation and tumorigenicity in breast cancer by modulating the G1/S phase transi-tion.28 E2F8 also conferred cisplatin resistance in ER+ breast cancer
cells.29 In the present study, E2F7 and E2F8 were significantly overex-pressed in breast cancer tissues, but their expression levels were not correlated with the tumor stage of the patients with breast cancer.
Figure 8. The Functions of E2Fs and Genes Significantly Associated with E2F Alterations
The functions of E2Fs and genes significantly associated with E2F alterations were predicted by the analysis of Kyoto Encyclopedia of Genes and Genomes (KEGG) by DAVID tools (https://david.ncifcrf.gov/summary.jsp).
Molecular Therapy
Figure 9. Cell Cycle and TGF-beta-Signaling Pathway Regulated by the E2F Alteration in Breast Cancer
The (A) cell cycle and (B) TGF-beta-signaling pathway regulated by the E2F alteration in breast cancer (cBioPortal) are shown.
www.moleculartherapy.org
Interestingly, high E2F7 and 8 expression was significantly correlated with poor OS, FP, PPS, and DMFS in all of the patients with breast cancer, indicating the oncogenic role of these TFs in breast cancer.
In this study, we systematically analyzed the expression and prognostic value of E2Fs in breast cancer, and we provided a thorough under-standing of the heterogeneity and complexity of the molecular biolog-ical properties of breast cancer. Our results indicated that the increased expression of E2F1, 2, and 8 in breast cancer tissues might play an important role in BC oncogenesis. High E2F1–3, 5, 7, and 8 expres-sions could also serve as molecular markers to identify high-risk sub-groups of patients with breast cancer. Our findings suggested that E2F1–3, 5, 7, and 8 were potential therapeutic targets for breast cancer, and transcriptional E2F4 and 6 were potential prognostic markers for the improvement of breast cancer survival and prognostic accuracy.