CCNA2 is a prognostic biomarker for ER+ breast cancer and tamoxifen resistance

Abstract

Identification of effective prognostic biomarkers and targets are of crucial importance to the management of estrogen receptor positive (ER+) breast cancer. CCNA2 (also known as CyclinA2) belongs to the highly conserved cyclin family and is significantly overexpressed in various cancer types. In this study, we demonstrated that CCNA2 had significant predictive power in distant metastasis free survival, disease free survival, recurrence free survival and overall survival of ER+ breast cancer patients. We also found that CCNA2 was closely associated with tamoxifen resistance. In addition, gene set enrichment analysis (GSEA) revealed that its expression was positively associated with genes overexpressed in endocrine therapy resistant samples. Finally, though CCNA2-Drug interaction network, we demonstrated the interactions between CCNA2 and several available cancer drugs. Overall, we suggest that CCNA2 is a biomarker for the prognosis of ER+ breast cancer and monitoring of tamoxifen efficacy. It's also a promising target for developing new strategies to prevent or even reverse tamoxifen resistance. Moreover, CCNA2 expression may help monitoring tamoxifen efficacy and directing personalized therapies. Nevertheless, in vivo and in vitro experiments and multi-center randomized controlled clinical trials are still needed before its application in clinical settings.

Figure 1. CCNA2 expression is associated with poor survival and tamoxifen resistance in ER+ breast cancer patients.

Kaplan-Meier plot for DMFS of ER+ (A), ER- (B) or tamoxifen treated (C) breast cancer patients grouped by the tertile of CCNA2 expression levels, significance was assessed by logrank test. (D) Log2 transformed mRNA expression values of CCNA2 in MCF-7 tumor xenografts treated with either tamoxifen or control. P values were calculated by unpaired two-tailed t test. Error bars represent mean ± SEM. (E) mRNA expression values of CCNA2 in tamoxifen resistant/sensitive MCF-7 subclones treated with tamoxifen or control. P values were calculated by unpaired two-tailed t test. Error bars represent mean ± SEM. (F) Gene set enrichment analysis of CCNA2 mRNA expression in relation to tamoxifen resistance gene set using breast cancer expression profiles (N = 2795).

Figure 2. Interaction network of CCNA2 and chemotherapeutic drugs.

The gene-drug interaction network shows us how available chemotherapeutic drugs could decrease the expression of CCNA2. For example, Doxorubicin could decrease the expression of CCNA2, while Oxaliplatin could increase the expression of CCNA2.