Journal
ANTICANCER RESEARCH
Volume 40, Issue 10, Pages 5471-5480Publisher
INT INST ANTICANCER RESEARCH
DOI: 10.21873/anticanres.14558
Keywords
MAD2L2; APC/C; TNBC
Categories
Funding
- Ariel Center for Applied Cancer Research (ACACR)
- Israeli Ministry of Aliya and Integration, Israel
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Background/Aim: Accurate regulation of the spindle assembly checkpoint (SAC) and anaphase promoting complex/cyclosome (APC/C) are essential for the correct execution of mitosis. In this work, we focused on MAD2L2 (REV7), a central translesion (TLS) protein, which also functions as a mitotic regulator by inhibiting APC/C in prometaphase. Materials and Methods: Using bioinformatics analysis, live cell imaging and APC/C protein binding and degradation assays, we explored the influence of MAD2L2 over-expression in breast cancer. Results: A significant overexpression of MAD2L2 was found in triple negative breast cancers (TNBC), compared to other breast cancers, correlating to poor patient prognosis. We also identified significant overexpression of MAD2L2 in the MDA-MB-157 triple negative (TN) cell line. A high percentage of MDA-MB-157 cells failed to complete mitosis and died during mitosis or shortly after. In addition, these cells completed mitosis at a significantly slower rate than control cells. MDA-MB-157 cells present high levels of mitotic slippage upon nocodazole treatment and acute dysregulation in APC/C function and substrate degradation. Moreover, silencing of MAD2L2 in the MDA-MB-157 cell line improved mitotic phenotypes. Conclusion: MAD2L2 overexpression supports the carcinogenic phenotype of MDA-MB157 cells by promoting uncontrolled mitosis.
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