E2F3 drives the epithelial-to-mesenchymal transition, cell invasion, and metastasis in breast cancer

Abstract

E2F3 is a transcription factor that may initiate tumorigenesis if overexpressed. Previously, we demonstrated that E2F3 mRNA is overexpressed in breast cancer and that E2F3 overexpression results in centrosome amplification and unregulated mitosis, which can promote aneuploidy and chromosome instability to initiate and sustain tumors. Further, we demonstrated that E2F3 leads to overexpression of the mitotic regulator Shugoshin-1, which until recently had unknown roles in cancer. This study aims to evaluate the roles of E2F3 and Shugoshin-1 in breast cancer metastatic potential. Here we demonstrated that E2F3 and Shugoshin-1 silencing leads to reduced cell invasion and migration in two mesenchymal triple-negative breast cancer (TNBC) cell lines (MDA-MB-231 and Hs578t). Moreover, E2F3 and Shugoshin-1 modulate the expression of epithelial-to-mesenchymal transition-associated genes such as Snail, E-Cadherin, and multiple matrix metalloproteinases. Furthermore, E2F3 depletion leads to reductions in tumor growth and metastasis in NOD- scid Gamma mice. Results from this study suggest a key role for E2F3 and a novel role for Shugoshin-1 in metastatic progression. These results can further help in the improvement of TNBC targeted therapies by interfering with pathways that intersect with the E2F3 and Shugoshin-1 signaling pathways.

IGF2BP3 enhances the mRNA stability of E2F3 by interacting with LINC00958 to promote endometrial carcinoma progression

“…To further explore the downstream genes of the LINC00958/IGF2BP3 axis in EC, we combined RNA sequencing results and genes coexpressed with IGF2BP3 from the TCGA database and discovered that E2F3 was the downstream effector. E2F3, as a member of a small family of transcription factors, is involved in the tumorigenesis of many malignancies [ 42 – 44 ]. Some studies have identified E2F3 as an oncogene that promotes the progression of EC [ 24 , 45 ].…”

Development of Gene Expression-Based Random Forest Model for Predicting Neoadjuvant Chemotherapy Response in Triple-Negative Breast Cancer

“…Inhibition of CDK2 has also been reported to be associated with growth inhibition in TNBC bearing mice [ 89 ] and reduced cell migration in TNBC cell lines [ 90 ]. E2F3 has been reported to be associated with doxorubicin responses [ 91 ] and EMT mechanisms in TNBC [ 92 ]. MCM2 and MCM3 have also been reported to have a role in DNA repair mechanisms in breast cancer [ 93 ], and these genes have also been reported as predictors of other NAC response predictive models [ 19 , 20 ].…”

E2F3 gene expression is a potential negative prognostic marker for localised and MYCN not‐amplified neuroblastoma: Results of in silico analysis of 786 samples

“…In particular, E2F3 expression has been consistently associated with proliferation, metastasis and drug resistance of many malignancies. [43][44][45][46][47][48] In NB, early evidence of the potential involvement of E2F3 in oncogenesis was provided by an in vitro study, which demonstrated that E2F3 binds the proximal MYCN promoter in NB cell lines expressing MYCN, 21 indicating that E2F3 is critical for the full activation of MYCN. 49 Consistently with this finding, our study showed a strong association between MYCN amplification and E2F3 expression.…”

“…The expression of the transcription factors E2Fs are frequently deregulated in human cancers. In particular, E2F3 expression has been consistently associated with proliferation, metastasis and drug resistance of many malignancies 43–48 …”