Breast cancer is a complex process involving multiple factors, one of the most critical aspects is the disorder of cell cycle regulation . Accurate prediction of prognosis is one of the most critical problems in breast cancer treatment. The prediction of breast cancer is closely related to the disease stage, and early diagnosis of the disease is crucial to the patient's prognosis. Once the risk of recurrence has been determined, it can be used to evaluate the potential effects of endocrine therapy, chemotherapy, or a combination of these treatments. The determination of accurate prognostic indicators will also influence the patient's individualized treatment. Also, identifying prognostic factors with potential biological significance can be used as therapeutic targets, which will be of great relevance to identifying and treating high-risk patients. The cell cycle is divided into several stages artificially, including G0/G1, S, G2, and M phase. Cyclins play different roles at different cell cycle stages depending on their sequence primitives, expression, and activation forms . Cyclins, along with the cyclin-dependent kinase (CDKs) and cyclin-dependent kinase inhibitors (CKIs), constitute the cycle regulation system to ensure the cell cycle orderly . The limitation point of transition from the G1 to the S1 phase is crucial for cell proliferation and differentiation . The primary function of Cyclin E is to regulate the restriction point "R" at the end of the G1-phase to allow cells to enter the S phase [51, 52]. The restriction point "R" was found to be the endpoint in the transition of the G1 to S phase of the cell cycle, which plays a crucial role in cell regulation and prevents the excessive and unrestricted proliferation of cells. It was found that overexpression of Cyclin E could accelerate the G1 phase of the cell cycle . The destruction of these pathways or the absence or overexpression of specific factors is closely related to the malignant transformation of cells and cancer development . Cyclin E expression levels are elevated significantly in many human tumors, manifested by amplification of the genome locus at which it is located (19q12-Q13) [55, 56], leading to widespread concern about its role in tumors. The over-expressed Cyclin E manifests as different molecular phenotypes in breast cancer and issue in the inactivation of the pRb pathway. A lower molecule form of Cyclin E derived from calpain induces a higher kinase activity [57, 58]. It has been pointed out that the oncogenic activity of Cyclin E can be inhibited by truncating the protein . At present, many studies have assessed that the overexpression of Cyclin E may be a prognostic factor of breast cancer patients. Most of the research shows that Cyclin E can indicate breast cancer prognosis, but other studies could not confirm this finding. The present meta-analysis is an updated one to investigate the correlation between Cyclin E expression and breast cancer prognosis.
In this study, a quantitative and systematic analysis was conducted on the published literature. Through reasonable inclusion and exclusion criteria, available literature was obtained, and relevant data were extracted. The correlation between the high expression of Cyclin E in breast cancer and prognosis and clinicopathological characteristics were analyzed systematically.
As the data are shown above, our meta-analysis results demonstrate that Cyclin E overexpression was statistically significantly associated with worse OS, BCSS, and RFS either in univariate or multivariate analysis in the overall population. In contrast to the previous two meta-analyses [60, 61]. Our results suggest that Cyclin E overexpression is associated with poor RFS, which is different from previous studies.
In the original studies, the authors used hazard ratios and risk ratios to analyze the association between Cyclin E and prognosis in breast cancer patients using univariate and multivariate analyses. RR is a measure of the strength of the association between exposure and outcome, that is, the ratio of morbidity or mortality in the exposed group to that in the non-exposed group, and applies to cohort studies or randomized controlled trials. RR indicates how many times the risk of morbidity or death in the exposed group is that of the non-exposed group. The more significant the RR value, the greater the effect of exposure, the stronger the association between exposure and outcome. The hazard ratio (HR), which is the ratio of the risk function of the exposed group to the non-exposed group, is generally obtained from the Cox proportional risk model. Most people think that HR and RR mean the same thing, but HR has a time factor. In other words, RR with time effect is HR. In the survival data, RR takes into account the difference in endpoint events, while HR takes into account the presence of endpoint events and the time taken to reach the endpoint. Therefore, there are differences between the two, and it is necessary to analyze them separately. Besides, in some literature, Cyclin E was a statistically significant prognostic indicator in univariate analysis, but not in multivariate analysis, so we also analyzed it from two aspects. Meanwhile, we also analyzed the relationship between Cyclin E and different clinical characteristics. Cyclin E overexpression was significantly correlated with age, ER status, menopausal status, and lymph node metastasis, but not with tumor size, PR status, disease stage, histological type, HER2 status, and nuclear grade.
Several limitations are present in this meta-analysis. First, cyclin E positivity was evaluated using different methods, antibodies, scoring methods, and high Cyclin E is defined according to the cut-off chosen by each author. Therefore, heterogeneities exist in cut-offs of a high level of cyclin E. Keyomarsi K et al.  reported that tumor cells often overexpress low-molecular-weight (LMW) cyclin E forms, which was obtained by cleaving Cyclin E with elastase . LMW has a high prognostic value in primary breast cancer [13, 22, 24]. However, some immunohistochemical assays lack antibodies to detect the amino terminus that may lead to the differences in the prognostic value of Cyclin E in previous studies. Second, the differences in selected patients, adjuvant therapy resulted in bias in the analysis. Moreover, all samples in the studies were obtained through modified radical mastectomy or breast-conserving surgery, and most of the studies clearly stated that no preoperative anti-tumor therapy had been given. Meanwhile, some articles did not mention preoperative treatment, which may affect the detection of Cyclin E. Therefore, the combined results should be interpreted with caution.