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Cyclin E, a redundant cyclin in breast cancer
J Gray-Bablin1, J Zalvide, M P Fox
1Division of Molecular Medicine, Wadsworth Center, Albany, NY 12201, USA.
Summary
Overexpressed cyclin E in breast tumors with high p16 can bypass normal cell cycle controls. This allows tumor cells to proliferate unchecked, contributing to cancer growth.
Area of Science:
- Molecular Biology
- Cell Biology
- Oncology
Background:
- Cyclin E and cyclin-dependent kinase (CDK) 2 regulate the G1/S transition in the mammalian cell cycle.
- Overexpression of cyclin E can lead to lower molecular weight isoforms active throughout the cell cycle.
- p16 overexpression in tumors can inactivate cyclin D/CDK complexes by sequestering CDK4/6.
Purpose of the Study:
- Investigate the role of cyclin E/CDK2 in breast cancer cells overexpressing p16.
- Determine if cyclin E can phosphorylate retinoblastoma susceptibility gene product (pRb) in these cells.
- Elucidate the mechanism by which cyclin E contributes to tumor growth advantage.
Main Methods:
- Analysis of breast cancer cell lines and tissues.
- Immunoprecipitation and kinase assays using cyclin E and pRb.
- Cell cycle synchronization and analysis of protein complexes.
Main Results:
- Constitutively active cyclin E/CDK2 complexes phosphorylate pRb throughout the cell cycle in p16-overexpressing breast tumors.
- pRb phosphorylation by cyclin E/CDK2 occurs despite p16-mediated inhibition of cyclin D/CDK complexes.
- Overexpressed cyclin E is found in p107/E2F complexes in tumor cells, but not normal cells.
Conclusions:
- Cyclin E/CDK2 complexes can functionally compensate for the loss of cyclin D-dependent kinase activity in phosphorylating pRb.
- Overexpression of cyclin E in p16-positive breast tumors bypasses the cyclin D/CDK/pRb feedback loop.
- This bypass mechanism provides a growth advantage to tumor cells.