CYCLIN D1 PROTEIN EXPRESSION AND FUNCTION IN HUMAN BREAST-CANCER

Cyclin D1 is a cell-cycle regulator essential for G(1) phase progressi on and a candidate proto-oncogene implicated in pathogenesis of severa l human tumour types, including breast carcinomas. In spite of the acc umulating genetic evidence, however, there are no data regarding abund ance and properties of the cyclin D1 protein in breast cancer. We now report aberrant nuclear overexpression/accumulation of the cyclin D1 p rotein in about half of the 170 primary breast carcinoma specimens ana lyzed by monoclonal antibody immunohistochemistry, indicating that the frequency of cyclin D1 abnormalities may be considerably higher than previously deduced from DNA amplification studies. A comparison of the expression patterns in matched lesions at different stages of tumour progression revealed that the cyclin D1 protein aberration appears to reflect a relatively early event and that, when acquired by a tumour, it is maintained throughout breast cancer progression including metast atic spread. In both tumour tissues nd breast cancer cell lines, the a bundance of this protein shows characteristic variations consistent wi th a cell-cycle oscillation and the peak levels expressed in G(1). In all 7 cell lines whose retinoblastoma (Rb) protein is mutant or comple xed to SV40 T antigen, exceptionally low levels of cyclin D1 protein a nd mRNA were found. Antibody-mediated and anti-sense oligonucleotide k nockout experiments demonstrate the requirement for the cell-cycle reg ulatory function of cyclin D1 in breast cancer lines with single or mu ltiple copies of the gene and reveal the absence of such a requirement in the cell lines with RB defects. Our data are consistent with the n otion that the emerging ''Rb-cyclin D1 pathway'' represents a frequent target on oncogenic abnormalities in breast cancer. (C) 1994 Wiley-Li ss, Inc.