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.

Cyclin E2 induces genomic instability by mechanisms distinct from cyclin E1

“…Given the strong role for mitotic disregulation and genome instability in human cancer, we characterized the effects of cyclin E2 on these endpoints in estrogen receptor-positive breast cancer cells, a subtype that overexpresses cyclin E2 more strongly than cyclin E1. 22 Intriguingly, we found that while cyclin E2 overexpression did not affect mitotic progression, the protein still induced genomic instability via mechanisms that are distinct from cyclin E1-induced genomic instability. nuclear envelopes, as marked by the distinct membranous localization of Lamin A/C (Fig.…”

“…models. 1,32 However cyclin E2 mRNA is detected at high levels independently of cyclin E1 mRNA in various malignancies, 20,22 and cyclin E2 repeatedly features in signatures of poor prognosis in breast cancer that do not include cyclin E1. [33][34][35] We show here that cyclins E1 and E2 have distinct effects on progression through mitosis when overexpressed.…”

“…21 In addition, cyclin E2 overexpression, but not cyclin E1 overexpression, is associated with shorter survival in some breast cancer subgroups and vice versa. 20,22 Several studies have shown that overexpression of cyclin E1 affects mitotic progression and promotes genomic instability, 7,9,10,23,24 but cyclin E2 has not been studied in this context. Given the strong role for mitotic disregulation and genome instability in human cancer, we characterized the effects of cyclin E2 on these endpoints in estrogen receptor-positive breast cancer cells, a subtype that overexpresses cyclin E2 more strongly than cyclin E1.…”

Analysis of factors affecting endocrine therapy resistance in breast cancer

“…The clinical data indicated that although there were BC-ERP patients who were suitable for endocrine therapy, ~30% of BC-ERP patients exhibited resistance to endocrine drugs in the early stages of treatment (primary resistance), and ~40% BC-ERP of patients showed the effectiveness of endocrine therapy prior to exhibiting gradually reduced sensitivity or resistance with the extension of treatment time (7,8). This ERP status greatly affected the clinical efficacy, and even lead to the failure of clinical BC treatment.…”

Overexpression of Cyclin E and its Low Molecular Weight Isoforms Cooperate with Loss of p53 in Promoting Oncogenic Properties of MCF-7 Breast Cancer Cells

“…Proper kinetics and expression level of cyclin E are crucial for its function during G1 to S phase transition, since its deregulated expression has been correlated with poor patient outcome in various human cancers including breast carcinoma (Keyomarsi and Pardee, 1993;Donnellan and Chetty, 1999;Caldon et al, 2012). In a retrospective studies, cyclin E level has been the best predictor of survival comparing with canonical clinical factors (age, tumor size, nodal status, stage of disease) and biologic markers (steroids and Her-2 receptor status, ploidy, proliferation index, cyclins D1 and D3) (Keyomarsi et al, 2002;Liu et al, 2013).…”