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.