Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells

• Published in: Molecular cancer therapeutics Vol. 11; no. 7; pp. 1488 - 1499
• Main Authors: Caldon, C Elizabeth, Sergio, C Marcelo, Kang, Jian, Muthukaruppan, Anita, Boersma, Marijke N, Stone, Andrew, Barraclough, Jane, Lee, Christine S, Black, Michael A, Miller, Lance D, Gee, Julia M, Nicholson, Rob I, Sutherland, Robert L, Print, Cristin G, Musgrove, Elizabeth A
• Format: Journal Article
• Language: English
• Published: United States 01.07.2012
• Subjects: Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - mortality; Breast Neoplasms - pathology; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin E - genetics; Cyclin-Dependent Kinase 2 - antagonists & inhibitors; Cyclins - genetics; Drug Resistance, Neoplasm - genetics; Estrogen Receptor Modulators - pharmacology; Female; Gene Expression; Gene Expression Profiling; Humans; Neoplasm Staging; Oncogene Proteins - genetics; Protein Kinase Inhibitors - pharmacology; Signal Transduction - drug effects
• DOI: 10.1158/1535-7163.MCT-11-0963
• ISSN: 1535-7163

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 RNAi-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.