期刊
EXPERIMENTAL BIOLOGY AND MEDICINE
卷 246, 期 19, 页码 2057-2071出版社
SAGE PUBLICATIONS LTD
DOI: 10.1177/15353702211035693
关键词
Shugoshin-1; triple-negative breast cancer; epithelial-to-mesenchymal transition; invasion
资金
- NIH/NCI [1F31CA247459-01, 5F31CA247459-02]
- NIGMS-RISE Training Program [R25GM082406]
- PRISE Program NIH-NIGMS [2R25GM096955]
- PRCTRC [2U54MD007587]
- PSMU54 Program from NIH [CA163071]
- MCC-U54 Program from NIH [CA163068]
- RCMI [G12MD007579]
- Hispanic Alliance for Clinical and Translational Research (Alliance) from NIGMS [U54GM133807]
- NIMHDNIAID [U54MD007587]
- Molecular Genomics (MAGIC) Core (MBCL-RCMI) [RR003050MD007579]
- Puerto Rico Science, Technology and Research Trust
- Ponce Medical School Foundation Inc. [2016-00026]
The study demonstrates that overexpression of E2F3 and Shugoshin-1 in breast cancer promotes tumor metastasis, while their silencing suppresses cell invasion and migration. Additionally, E2F3 and Shugoshin-1 regulate the expression of genes associated with epithelial-to-mesenchymal transition.
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.
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