CYCLIN D1 AND RETINOBLASTOMA GENE-EXPRESSION IN HUMAN BREAST-CARCINOMA - CORRELATION WITH TUMOR PROLIFERATION AND ESTROGEN-RECEPTOR STATUS

Cyclin D1 (CCND1) and retinoblastoma (Rb) genes are cell cycle regulat ors which are altered in some breast carcinomas. However, the possible cooperation between CCND1 and Rb, as well as the influence and coinci dence of their abnormalities in the proliferative capacity of mammary carcinoma cells in vivo, is still unknown. In order to assess both the significance of the CCND1 gene and Rb alterations in breast carcinoma s and their relationship with the proliferative capacity of the tumour s and other clinico-pathological factors, CCND1 mRNA expression was st udied in 46 cases of primary breast carcinomas and matched normal tiss ue, 45 of which were also studied immunohistochemically. Rb expression was analysed in the same cases by immunohistochemistry, whereas the p roliferative activity of the carcinomas was evaluated by flow cytometr y. CCND1 mRNA mas overexpressed in 19 tumours (41 per cent). Sixteen c ases showed diffuse immunohistochemical expression, ten carcinomas had few positive cells, and 19 mere absolutely negative. CCND1 mRNA and p rotein overexpression was associated with oestrogen receptor (ER) expr ession by the tumour. Interestingly, lack of ER expression was associa ted with a decreased CCND1 mRNA signal in non-overexpressed tumours. N o association was observed between CCND1 mRNA or protein overexpressio n and tumour proliferation or other clinico-pathological parameters. L oss of Rb expression was observed in 26 per cent of the tumours. This abnormality was significantly associated with increased mean S-phase ( P=0.017) and decreased CCND1 mRNA expression in non-overexpressed tumo urs, supporting in vivo the postulated regulatory loop between Rb and CCND1 in vitro. We conclude that CCND1 up-regulation is not associated with increased proliferative activity in breast carcinomas, whereas i ts expression might be regulated in vice by hormones and Rb. Loss of R b expression is significantly associated with an increased proliferati on of tumour cells, suggesting an important role in the progression of a subset of breast carcinomas, regardless of CCND1 abnormalities. (C) 1997 by John Wiley & Sons, Ltd.