title: Cyclin E2 overexpression is associated with endocrine resistance but not insensitivity to CDK2 inhibition in human breast cancer cells.
abstract: 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.
authors.affiliation: The Kinghorn Cancer Centre and Cancer Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
authors.forename: C Elizabeth
authors.initials: CE
authors.lastname: Caldon
authors.forename: C Marcelo
authors.initials: CM
authors.lastname: Sergio
authors.forename: Jian
authors.initials: J
authors.lastname: Kang
authors.forename: Anita
authors.initials: A
authors.lastname: Muthukaruppan
authors.forename: Marijke N
authors.initials: MN
authors.lastname: Boersma
authors.forename: Andrew
authors.initials: A
authors.lastname: Stone
authors.forename: Jane
authors.initials: J
authors.lastname: Barraclough
authors.forename: Christine S
authors.initials: CS
authors.lastname: Lee
authors.forename: Michael A
authors.initials: MA
authors.lastname: Black
authors.forename: Lance D
authors.initials: LD
authors.lastname: Miller
authors.forename: Julia M
authors.initials: JM
authors.lastname: Gee
authors.forename: Rob I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Cristin G
authors.initials: CG
authors.lastname: Print
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019927:Cyclin E / Q000235:genetics; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors*; D016213:Cyclins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D009367:Neoplasm Staging; D015513:Oncogene Proteins / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C475820:CCNE1 protein, human; C503688:CCNE2 protein, human; D019927:Cyclin E; D016213:Cyclins; D020847:Estrogen Receptor Modulators; D015513:Oncogene Proteins; D047428:Protein Kinase Inhibitors; D051357:Cyclin-Dependent Kinase 2