Estrogen regulation of cell cycle progression in breast cancer cells.
Estrogens are potent mitogens in a number of target tissues including the mammary gland where they play a pivotal role in the development and progression of mammary carcinoma. The demonstration that estrogen-induced mitogenesis is associated with the recruitment of non-cycling, G0, cells into the cell cycle and an increased rate of progression through G1 phase, has focused attention on the estrogenic regulation of molecules with a known role in the control of G1-S phase progression. These experiments provide compelling evidence that estrogens regulate the expression and function of c-Myc and cyclin D1 and activate cyclin E-Cdk2 complexes, all of which are rate limiting for progression from G1 to S phase. Furthermore, these studies reveal a novel mechanism of activation of cyclin E-Cdk2 complexes whereby estrogens promote the formation of high molecular weight complexes lacking the CDK inhibitor p21. Inducible expression of either c-Myc or cyclin D1 can mimic the effects of estrogen in activating the cyclin E-Cdk2 complexes and promoting S phase entry, providing evidence for distinct c-Myc and cyclin D1 pathways in estrogen-induced mitogenesis which converge on the activation of cyclin E-Cdk2. These data provide new mechanistic insights into the known mitogenic effects of estrogens and identify potential downstream targets that contribute to their role in oncogenesis.
Prall
O W
OW
Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW, Australia.
Rogan
E M
EM
Sutherland
R L
RL
D000818:Animals; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects*; D019938:Cyclin D1 / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D008325:Mammary Neoplasms, Experimental / Q000209:etiology / Q000473:pathology*; D008934:Mitogens / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism
D019927:Cyclin E; D004967:Estrogens; D008934:Mitogens; D016271:Proto-Oncogene Proteins c-myc; D019938:Cyclin D1; D017346:Protein Serine-Threonine Kinases; D042846:CDC2-CDC28 Kinases; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases