Document Detail

Mechanisms of growth arrest by c-myc antisense oligonucleotides in MCF-7 breast cancer cells: implications for the antiproliferative effects of antiestrogens.
MedLine Citation:
PMID:  12036924     Owner:  NLM     Status:  MEDLINE    
The proto-oncogene c-myc is up-regulated by estrogen stimulation of hormone-dependent breast cancer cells and is frequently overexpressed in breast and other cancers. Therapeutic interventions that inhibit c-Myc expression have been extensively investigated, including antisense oligonucleotides that have high specificity and potential clinical application. This investigation compared antiestrogen-mediated growth arrest with the molecular events after repression of c-Myc expression in MCF-7 breast cancer cells using an antisense oligonucleotide. We show that the decreased cellular proliferation of MCF-7 cells after direct inhibition of c-Myc is a consequence of inhibition of cyclin D1 expression, subsequent redistribution of p21(WAF1/CIP1) from cyclin D1-Cdk4 to cyclin E-Cdk2 complexes, and a decline in cyclin E-Cdk2 enzymatic activity. Simultaneous repression of p21(WAF1/CIP1) can attenuate the growth-inhibitory effects of reduced c-Myc expression emphasizing the importance of this cyclin-dependent kinase (CDK) inhibitor in growth arrest. These molecular events are similar to the initial changes in cyclin gene expression, CDK complex formation and CDK activity seen after antiestrogen (ICI 182780)-mediated growth inhibition of MCF-7 cells, which suggests that the down-regulation of c-Myc by ICI 182780 is a primary event that culminates in cell cycle arrest.
Jason S Carroll; Alexander Swarbrick; Elizabeth A Musgrove; Robert L Sutherland
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cancer research     Volume:  62     ISSN:  0008-5472     ISO Abbreviation:  Cancer Res.     Publication Date:  2002 Jun 
Date Detail:
Created Date:  2002-05-30     Completed Date:  2002-07-16     Revised Date:  2013-06-11    
Medline Journal Info:
Nlm Unique ID:  2984705R     Medline TA:  Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3126-31     Citation Subset:  IM    
Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, 384 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.
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MeSH Terms
Breast Neoplasms / drug therapy,  genetics*,  pathology*
CDC2-CDC28 Kinases*
Cell Cycle Proteins / metabolism
Cell Division / drug effects,  genetics
Cyclin D1 / biosynthesis,  genetics,  metabolism
Cyclin E / biosynthesis,  genetics,  metabolism
Cyclin-Dependent Kinase 2
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinase Inhibitor p27
Cyclin-Dependent Kinases / metabolism
Cyclins / biosynthesis,  genetics,  metabolism
Estradiol / analogs & derivatives*,  pharmacology
Estrogen Receptor Modulators / pharmacology*
Gene Expression Regulation, Neoplastic
Genes, myc / drug effects,  genetics*
Oligonucleotides, Antisense / genetics,  pharmacology*
Protein-Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins*
Proto-Oncogene Proteins c-myc / antagonists & inhibitors*,  biosynthesis,  genetics
RNA, Messenger / genetics,  metabolism
Tumor Suppressor Proteins / metabolism
Reg. No./Substance:
0/CDKN1A protein, human; 0/Cell Cycle Proteins; 0/Cyclin E; 0/Cyclin-Dependent Kinase Inhibitor p21; 0/Cyclins; 0/Estrogen Receptor Modulators; 0/Oligonucleotides, Antisense; 0/Proto-Oncogene Proteins; 0/Proto-Oncogene Proteins c-myc; 0/RNA, Messenger; 0/Tumor Suppressor Proteins; 136601-57-5/Cyclin D1; 147604-94-2/Cyclin-Dependent Kinase Inhibitor p27; 22X328QOC4/fulvestrant; 50-28-2/Estradiol; EC Kinases; EC Kinases; EC protein, human; EC protein, human; EC Kinase 2; EC Kinase 4; EC Kinases

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