DEREGULATION OF CYCLIN-E AND CYCLIN-D1 IN BREAST-CANCER IS ASSOCIATEDWITH INACTIVATION OF THE RETINOBLASTOMA PROTEIN

Inactivation of the retinoblastoma protein (pRB) by mutations or abnor mal phosphorylation is a mechanism by which tumour cells can subdue no rmal growth control. Among molecules involved in control of pRB phosph orylation, cyclin D1 and E have been found to be deregulated and overe xpressed in various types of cancers. In order to study the cell cycle regulatory mechanisms in breast cancer, we have analysed the protein expression of cyclin D1 and E in 114 tumour specimens from patients wi th primary breast cancer using Western blotting. Twenty-five out of 34 tumours with overexpression of cyclin E showed uniform low cyclin D1 expression, and by immunohistochemical analysis of pRB we present evid ence for the existence of pRB defects in approximately 40% of these tu mours in contrast to no PRE defects in the other group of tumours. Thi s result was supported by a high protein expression of the cyclin-depe ndent kinase inhibitor p16 in 44% of the tumours with high cyclin E an d low D1 expression, and all immunohistochemical pRB defect tumours sh owed a high p16 protein level. Additionally, an abnormal low pRB phosp horylation in relation to a high proliferative activity and loss of he terozygosity of the retinoblastoma susceptibility gene locus were foun d in all but one tumour with immunohistochemical defect pRB. Interesti ngly, tumours with high cyclin E and low D1 expression were generally oestrogen receptor negative suggesting a role for cell cycle regulator s in the mechanisms leading to oestrogen independent tumour growth. Fu rthermore, the prognosis differed markedly for the patients in the var ious groups of tumours, indicating that the heterogeneous nature of br east cancer pathogenesis and the clinical course in part could be expl ained by different and distinctive sets of cell cycle defects.