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.
Highlights
The introduction of tamoxifen as a treatment for hormone receptor–positive breast cancer led to significant decreases in breast cancer mortality over the last 30 years
The basal-like subtype expressed the highest levels of CCNE1, whereas levels of CCNE2 were similar in Her2 and basal-like cancers (Fig. 1A, Supplementary Table S2)
Activation of CDK2 has been implicated in acquired resistance to CDK4 inhibition [20], and we show here that overexpression of cyclin E1 or E2 reduces sensitivity to CDK4 inhibition in breast cancer cells
Summary
The introduction of tamoxifen as a treatment for hormone receptor–positive breast cancer led to significant decreases in breast cancer mortality over the last 30 years. A pervasive feature of tamoxifen-resistant breast cancers is increased expression of genes related to proliferation, including cyclin D1, and gene sets regulated by MYC, E2F, and RB, suggesting a important role for genes involved in the G1–S transition of the cell cycle [1,2,3,4,5,6]. Endocrine-resistant breast cancer is one disease subtype in which cyclin-dependent kinase (CDK) inhibitors with specificity for the cyclin D1-associated kinases CDK4 and CDK6 may offer significant clinical benefit [7]. A further understanding of the major drivers of proliferation in breast cancer cells and direct targeting of the pathways they control are likely to provide mechanisms for identifying and treating endocrine-refractory breast cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
