Evaluation of CCND1 amplification and CyclinD1 expression: diffuse and strong staining of CyclinD1 could have same predictive roles as CCND1 amplification in ER positive breast cancers

CCND1 is amplified in around 10-20% of primary breast cancers and preferentially occurs in ER positive tumors. Though CCND1 amplification was reported predicting poor response of adjuvant tamoxifen treatment and poor prognosis in ER positive breast cancers, there were controversial data regarding the predicting value of CyclinD1 protein overexpression. In this study, we detected CyclinD1 expression using immunohistochemistry and CCND1 gene copy number using fluorescence in situ hybridization (FISH) in 355 invasive breast cancers with foci ductal carcinoma in situ (DCIS). CCND1 amplification was founded in 52 (14.6%) cases all of which showed moderate to strong CyclinD1 expression. However, majority of CCND1- tumors exhibited mild to moderate CyclinD1 staining. There were identical alterations in DCIS and the invasive lesions within the same tumor. CCND1 amplification was positively correlated with ER, PR and lymph node status (P<0.001) while negatively correlated with HER-2 amplification and p53 status (P<0.05). The majority of the CCND1 amplification/high CyclinD1 breast cancers were luminal B type while basal-like type often lost the expression of this protein. The ROC curve analysis showed that a cut-off point at which the immunostaining score of CyclinD1 is 6.5 could predict CCND1 gene amplification in breast cancer. This study indicated loss expression of CyclinD1 might be an important event in the tumorigenesis in basal-like breast cancers. Further, we confirmed an optimal cut-off point of immunostaining scores of CyclinD1 protein which could be used to predict the status of CCND1 gene and identify a subgroup of ER positive breast cancers with poor response to endocrine agents.