Ectopic expression of cyclin E in estrogen responsive cells abrogates antiestrogen mediated growth arrest.
Estrogens stimulate proliferation of estrogen receptor positive MCF7 breast cancer cells while antiestrogens signal a G0/G1 growth arrest. In MCF7 cells, arrest is mediated through the CDK inhibitors p21 and p27 and through a decrease in cyclin E/CDK2 kinase activity. We found that in MCF7 cells, overexpression of cyclin E partially abrogates a tamoxifen mediated growth arrest. Overexpression of cyclin E is accompanied by a decrease in the levels of RB and CDK inhibitor p21 but an increase in CDK inhibitor p27. Cyclin E overexpression also alters the composition of E2F transcription factor complexes. The E2F4/p107/cyclin E/CDK2 complex, a minor component in proliferating control cells that is absent in growth-arrested cells, is more abundant in both proliferating and tamoxifen treated cyclin E overexpressing cells. Conversely, levels of the quiescence associated E2F/p130 complex is not detected in these cells. Expression from the E2F dependant promoter is elevated in proliferating and tamoxifen treated cyclin E overexpressing cells. This study suggests that a modest overexpression of cyclin E abrogates the tamoxifen mediated growth arrest through modification of the RB/E2F pathway. Moreover, these results provide one explanation of why some cells that express the estrogen receptor may be unresponsive to antiestrogens.
Dhillon
Navdeep K
NK
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, Davis, California, CA 95616, USA.
Mudryj
Maria
M
D042846:CDC2-CDC28 Kinases; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism*; D051357:Cyclin-Dependent Kinase 2; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050704:E2F4 Transcription Factor; D024202:Electrophoretic Mobility Shift Assay; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D004967:Estrogens / Q000378:metabolism*; D006801:Humans; D046911:Macromolecular Substances; D009687:Nuclear Proteins / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050704:E2F4 Transcription Factor; C493762:E2F4 protein, human; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D046911:Macromolecular Substances; D009687:Nuclear Proteins; C493844:RBL1 protein, human; D012333:RNA, Messenger; D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107; D014157:Transcription Factors; D013629:Tamoxifen; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases