Cell cyclins and cyclin-dependent kinase activities in mouse mammary tumor development.

Breast cancer in humans, as in mice and rats, is thought to be the result of sequential changes in the epithelial cells of the mammalian glands. This study examines the altered expression or activation of cell cycle related proteins in an in situ system composed of hyperplasia, preneoplasia and neoplasia of mouse mammary glands. The results showed a high level of cdc2/cdk2 kinase activities in tumors compared to hyperplasias which was independent of cdc2/cdk2 protein levels. Some of the cdk-associated proteins which are thought to regulate cdk kinase activity were examined in these tissues. Cyclin A was overexpressed in all hyperplasias irrespective of their tumorigenic potentials. However, a number of alterations in cyclin E protein were associated with cdk2 and its associated kinase activity during mammary tumorigenesis. First, the level of normal cyclin E (p50) expression was positively correlated with the tumorigenic potentials of different hyperplasia lines. Second, several cyclin E isoforms (p48, p43, p35, p34, p32) were detected only in tumor tissues. Third, a 2.3- and 8.3-fold increase in cyclin E-associated cdk2 kinase activity was present in highly tumorigenic hyperplasias and neoplasias respectively compared to the low tumorigenic hyperplasias. Polymorphic cell nuclear antigen (PCNA) protein bound to cdk2 was a better indicator for cell proliferation and cdk2 kinase activity than the PCNA labeling index. These results suggest a sequential pattern of multiple derangements in factors regulating cdk2 protein function during mammary tumorigenesis. High levels of cdk2 kinase activity are observed only in tumors and appear to be closely related to alterations in cyclin E protein expression.