Journal
MOLECULAR CANCER THERAPEUTICS
Volume 11, Issue 7, Pages 1488-1499Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-11-0963
Keywords
-
Categories
Funding
- NHMRC (Australia) project [481307, 535903, 427601]
- Cancer Institute NSW Career Development Fellowship [07/CDF/1-28, 11/CDF/3-26]
- Translational program grant [10/TPG/104]
- National Breast Cancer Foundation/Cure Cancer Australia Fellowship
- Young Garvan Fellowship
- Breast Cancer Campaign (United Kingdom) Scientific Fellowship [2010MaySF05]
- Cardiff University
- New Zealand Breast Cancer Research Trust project grant [3621880]
- Australian Cancer Research Foundation
- RT Hall Trust
- Petre Foundation
- Breast Cancer Campaign [2010MaySF05] Funding Source: researchfish
Ask authors/readers for more resources
Cyclin E2, but not cyclin E1, is included in several gene signatures that predict disease progression in either tamoxifen-resistant or metastatic breast cancer. We therefore examined the role of cyclin E2 in antiestrogen resistance in vitro and its potential for therapeutic targeting through cyclin-dependent kinase (CDK) inhibition. High expression of CCNE2, but not CCNE1, was characteristic of the luminal B and HER2 subtypes of breast cancer and was strongly predictive of shorter distant metastasis-free survival following endocrine therapy. After antiestrogen treatment of MCF-7 breast cancer cells, cyclin E2 mRNA and protein were downregulated and cyclin E2-CDK2 activity decreased. However, this regulation was lost in tamoxifen-resistant (MCF-7 TAMR) cells, which overexpressed cyclin E2. Expression of either cyclin E1 or E2 in T-47D breast cancer cells conferred acute antiestrogen resistance, suggesting that cyclin E overexpression contributes to the antiestrogen resistance of tamoxifen-resistant cells. Ectopic expression of cyclin E1 or E2 also reduced sensitivity to CDK4, but not CDK2, inhibition. Proliferation of tamoxifen-resistant cells was inhibited by RNAl-mediated knockdown of cyclin E1, cyclin E2, or CDK2. Furthermore, CDK2 inhibition of E-cyclin overexpressing cells and tamoxifen-resistant cells restored sensitivity to tamoxifen or CDK4 inhibition. Cyclin E2 overexpression is therefore a potential mechanism of resistance to both endocrine therapy and CDK4 inhibition. CDK2 inhibitors hold promise as a component of combination therapies in endocrine-resistant disease as they effectively inhibit cyclin E1 and E2 overexpressing cells and enhance the efficacy of other therapeutics. Mol Cancer Ther; 11(7); 1488-99. (c) 2012 AACR.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available