Prognostic value of combined analysis of cyclin D1 and estrogen receptor status in breast cancer patients

Abstract

The amplification of cyclin D1, located on chromosome 11q13, in breast cancer patients has been found to be associated with reduced relapse-free and overall survival; however, there still exists strong controversy about these findings. In order to evaluate the prognostic value of cyclin D1 and other prognostic variables in human breast cancers, we have assessed estrogen receptor (ER) status, cyclin D1, c-erbB2 and p53 overexpression in 175 primary breast carcinomas, and investigated the relationships of prognostic variables to the patient clinical outcome and the association between cyclin D1 overexpression and other prognostic variables. There was some degree of variability in staining intensities and proportions within the same tumor. The overexpression of both cyclin D1 and ER revealed a significantly prolonged survival in univariate analysis (P = 0.020). Among the various prognostic variables, distant metastasis showed a statistically significant association with overall survival. A significant correlation was observed between cyclin D1 overexpression and small size of the primary tumor (P = 0.031), low Bloom and Richardson's histological grade (P = 0.001), and positive ER status (P = 0.000). In contrast to what was previously expected, the present study suggests that the overexpression of cyclin D1 has a tendency to have a positive clinical outcome and a potential role in identifying a subset of patients predicting a good prognosis, particularly when ER is coexpressed.

Cyclin D1 expression is associated with poor prognostic features in estrogen receptor positive breast cancer

“…High cyclin D1 expression has been associated with less aggressive tumour characteristics including hormone receptor positivity. It has associated with low tumour grade [4,6,7,14], although a few studies have failed to confirm this [3,5,11]. The role of cyclin D1 in breast cancer prognosis remains unclear; some studies show correlation to poor, some to good prognosis, and some have not been able to show any correlation.…”

“…High cyclin D1 expression is associated with non-aggressive features in breast cancer including estrogen receptor (ER) positivity [3][4][5][6][7][8]. Estrogen stimulates cyclin D1 expression and cyclin D1 is an important mediator of estrogen stimulation of cell cycle progression [9].…”

Cyclin D1 protein overexpression and CCND1 amplification in breast carcinomas: an immunohistochemical and chromogenic in situ hybridisation analysis

“…Conflicting results on the prognostic impact of cyclin D1 overexpression and clinical outcome in breast cancer patients have been reported. 1,11,[16][17][18][19][20][21][37][38][39] Despite the known problems with commercially available anticyclin D1 antibodies, a considerable amount of data linking cyclin D1 overexpression with lack of response to tamoxifen have been published. 13,14 After several attempts at optimising mouse monoclonal and rabbit polyclonal antibodies to cyclin D1, we have attained reproducible results with the rabbit monoclonal antibody employing the protocol described by Cheuk et al 28 In contrast to other antibodies, the new rabbit anticyclin D1 monoclonal antibody shows a strong correlation with CCND1 gene amplification.…”

“…Patients whose tumours displayed strong and moderate cyclin D1 expression showed significantly longer OS than those with no or weak expression, which is in agreement with previous studies. 1,19,37 However, others have found an association between cyclin D1 overexpression and poorer clinical outcome. 23,48 This discrepancy may stem from the use of different antibodies, different thresholds for Cyclin D1 positivity and different methods for the analysis of Cyclin D1 expression (Western blotting vs imunohistochemistry in the present study and others).…”

Tissue microarray analyses of G1/S-regulatory proteins in ductal carcinoma in situ of the breast indicate that low cyclin D1 is associated with local recurrence

“…Most studies delineating the prognostic importance for cyclin D1 overexpression in breast cancer have been performed using invasive tumours and the results are diverging: some studies indicate that cyclin D1 overexpression is associated with a negative clinical outcome (Ohta et al, 1997;Kenny et al, 1999), some show no prognostic significance (Michalides et al, 1996;van Diest et al, 1997), while others report a better prognosis for cyclin D1 high tumours (Gillett et al, 1996;Hwang et al, 2003). One explanation for the discrepancy could be that the fraction of patients treated with antioestrogens varied between different studies and recent experimental findings (Bindels et al, 2002;Hui et al, 2002) suggest that cyclin D1 overexpression could induce resistance to antioestrogen treatment.…”