Cyclin-E is a strong predictor of endocrine therapy failure in human breast cancer

Abstract

Recently, cyclin-E was reported to be the most prominent prognostic factor for breast cancer outcome described so far, even surpassing axillary nodal involvement. Earlier studies on the prognostic value of cyclin-E in breast cancer, however, yielded heterogeneous results. Therefore, we set out to confirm and extend these results by quantitative Taqman RT-PCR of cyclin-E levels in 277 resectable breast cancers. Cyclin-E levels were not associated with relapse-free survival (RFS) or overall survival (OS) in the total cohort of patients, or in the subset of patients without involved lymph nodes that were not treated with adjuvant systemic therapy. Besides several classical clinicopathological factors, the interaction between cyclin-E and adjuvant endocrine therapy (P ¼ 0.01, HR ¼ 3.04, 95% CI: 1.30-7.09) was found to contribute significantly in multivariate analyses. Cyclin-E levels were associated with poor RFS specifically in patients treated with adjuvant endocrine therapy (n ¼ 108, P ¼ 0.001, HR ¼ 4.01, 95% CI: 1.76-9.12), independent of estrogen receptor status. In conclusion, cyclin-E is not a pure prognostic factor in breast cancer, but rather a predictor of failure of endocrine therapy. Differences in literature on the presumed prognostic value of cyclin-E may be due to differences in treatment. Assessment of cyclin-E levels can aid in improving adjuvant treatment selection.

Impact of cyclins E, neutrophil elastase and proteinase 3 expression levels on clinical outcome in primary breast cancer patients

“…5,[24][25][26][27] We showed that CCNE1 and CCNE2 were both associated with RFI in a univariate analysis, whereas CCNE2 was the only significant variable in the multivariate model. However, when CCNE2 was discarded, CCNE1 became significant.…”

“…The histological grade, as well as the ER status was significantly associated with clinical outcome in univariate analysis. All these variables were further compared in a multivariate model with backward stepwise selection based on hypotheses tests using likelihood ratios, starting only with the variables that had a As several studies reported CCNE and NE as markers predicting endocrine therapy failure, 5,9 we conducted a subgroup analysis in the 110 ER-positive tumors from patients treated with adjuvant tamoxifen only. The results regarding NE, PR3, CCNE1 and CCNE2 were visualized as Kaplan-Meier curves in Figure 2.…”

“…4) and with endocrine therapy failure. 5 Recent studies identified low molecular weight isoforms (LMW) of CCNE, generated specifically in tumors by elastase-mediated proteolytic processing, 6 which were shown to be hyperactive compared to full-length CCNE and associated with poor clinical outcome in stage I to III breast cancer patients. 7 Recently, it has been shown that high levels of neutrophil elastase (NE) protein in breast cancer tissue extracts were associated with poor clinical outcome and with endocrine treatment failure in patients with advanced breast cancer disease.…”

Impaired p53 function leads to centrosome amplification, acquired ERα phenotypic heterogeneity and distant metastases in breast cancer MCF-7 xenografts

“…Aberrant expression of cyclins is linked to breast cancer development and progression (Bindels et al, 2002;Akli et al, 2004;Caldon et al, 2006). While cyclin D1 overexpression is generally associated with an ERapositive phenotype and favorable clinical outcome, deregulation of cyclin E and A is linked to induction of centrosome amplification, aneuploidy, loss of ERa and poor outcome (Bindels et al, 2002;Span et al, 2003;Joe et al, 2005). One mechanism for preservation of genomic stability is through p53-mediated control of centrosome homeostasis (Fukasawa, 2005).…”

Expression of Cyclin E Renders Cyclin D-CDK4 Dispensable for Inactivation of the Retinoblastoma Tumor Suppressor Protein, Activation of E2F, and G1-S Phase Progression

“…A recent report from Keyomarsi et al (75) argues convincingly that cyclin E expression levels are the single most powerful clinical parameter in predicting long term prognosis in breast cancer patients, with high levels of cyclin E having an even higher hazard ratio than the classic prognostic indicators cyclins D1 and D3, HER-2/neu, estrogen/progesterone receptor status, and lymph node metastases (75). Supplementing that argument, Span et al (76) recently reported that the expression level of cyclin E is a strong predictor of endocrine therapy failure in breast cancer patients, a result that builds upon mounting that evidence that cyclin E is a critical target of endocrine signaling in promoting steroid hormone-dependent tumor growth (77). Finally, 10 percent of mice that express a human cyclin E transgene develop carcinoma (78), and cyclin E knockout MEFs are strikingly resistant to transformation with oncogenic Ras (Ref.…”