Cyclin E expression in breast cancer:: predicting germline BRCA1 mutations, prognosis and response to treatment

Background: Elevated levels of the cell cycle protein cyclin E, and low levels of its inhibitor, P27(Kip1), have been associated with a poor prognosis following breast cancer. Some studies have found that germline mutations in the breast cancer susceptibility gene, BRCA1, are also associated with an inferior survival rate. The relationship between cyclin E/p27(Kip1) levels, BRCA1 status and outcome has not been studied in detail. Patients and methods: We analyzed a historical cohort of 288 Ashkenazi Jewish women who were diagnosed with breast cancer between 1980 and 1995 and were previously tested for BRCA1/2 mutations. Protein levels of cyclin E and p27(KiP1) were assessed by immunohistochemistry. Breast cancer-specific survival (BCSS) was the main outcome measured. Results: The median follow-up was 8 years. Thirty tumors carried germline BRCA1 mutations. These tumors were more likely to have high cyclin E protein levels [odds ratio (OR) 9.5; P < 0.001] and low p27(Kip1) protein levels (OR 2.8; P = 0.03) than tumors from patients without BRCA1/2 mutations. High cyclin E expression level was the strongest predictor of BRCA1 germline mutations (multivariate OR 4.7; P = 0.004). On univariate analysis, high cyclin E protein levels [relative risk (RR) 2.6; P < 0.001] and low p27(Kip1) protein levels (RR 2.3; P = 0.006) were significant prognostic factors for a poorer BCSS. In Cox multivariate models, high cyclin E levels remained an independent indicator of poor outcome only in the subgroup of patients who did not receive chemotherapy (P = 0.002). Conclusions: In this ethnically restricted cohort, a high level of cyclin E is a characteristic of BRCA1-related breast cancer, and is a marker of poor prognosis following breast cancer, particularly in the absence of adjuvant chemotherapy.