Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression.
Cyclins and proto-oncogenes including c-myc have been implicated in eukaryotic cell cycle control. The role of cyclins in steroidal regulation of cell proliferation is unknown, but a role for c-myc has been suggested. This study investigated the relationship between regulation of T-47D breast cancer cell cycle progression, particularly by steroids and their antagonists, and changes in the levels of expression of these genes. Sequential induction of cyclins D1 (early G1 phase), D3, E, A (late G1-early S phase), and B1 (G2 phase) was observed following insulin stimulation of cell cycle progression in serum-free medium. Transient acceleration of G1-phase cells by progestin was also accompanied by rapid induction of cyclin D1, apparent within 2 h. This early induction of cyclin D1 and the ability of delayed administration of antiprogestin to antagonize progestin-induced increases in both cyclin D1 mRNA and the proportion of cells in S phase support a central role for cyclin D1 in mediating the mitogenic response in T-47D cells. Compatible with this hypothesis, antiestrogen treatment reduced the expression of cyclin D1 approximately 8 h before changes in cell cycle phase distribution accompanying growth inhibition. In the absence of progestin, antiprogestin treatment inhibited T-47D cell cycle progression but in contrast did not decrease cyclin D1 expression. Thus, changes in cyclin D1 gene expression are often, but not invariably, associated with changes in the rate of T-47D breast cancer cell cycle progression. However, both antiestrogen and antiprogestin depleted c-myc mRNA by > 80% within 2 h. These data suggest the involvement of both cyclin D1 and c-myc in the steroidal control of breast cancer cell cycle progression.
Musgrove
E A
EA
Cancer Biology Division, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
Hamilton
J A
JA
Lee
C S
CS
Sweeney
K J
KJ
Watts
C K
CK
Sutherland
R L
RL
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000096:biosynthesis / Q000235:genetics; D042846:CDC2-CDC28 Kinases; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics*; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D016259:Genes, myc; D006133:Growth Substances / Q000494:pharmacology*; D006657:Histones / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D015735:Mifepristone / Q000494:pharmacology*; D053284:Polyunsaturated Alkamides; D011282:Pregnenediones / Q000494:pharmacology*; D045167:Progesterone Congeners / Q000494:pharmacology; D011494:Protein Kinases / Q000096:biosynthesis / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
D016213:Cyclins; D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; D006133:Growth Substances; D006657:Histones; D007328:Insulin; D053284:Polyunsaturated Alkamides; D011282:Pregnenediones; D045167:Progesterone Congeners; D012333:RNA, Messenger; D011994:Recombinant Proteins; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; D015735:Mifepristone; D004958:Estradiol; C051781:ICI 164384; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases