Glucocorticoids stabilize HER-2/neu messenger RNA in human epithelial ovarian carcinoma cells.
Recent evidence suggests that HER-2/neu oncogene overexpression may have a direct role in the pathogenesis of ovarian cancer rather than being merely a prognosticator of poor disease outcome. The mechanisms regulating expression of the p185HER-2/neu growth factor receptor protein are poorly understood. Glucocorticoid receptors are present in tumor cells of almost 90% of ovarian cancers, and these hormones inhibit ovarian cancer cell growth. Glucocorticoid regulation of HER-2/neu expression was investigated using the SK-OV-3 human epithelial ovarian cancer cell line in which the HER-2/neu gene is amplified five- to eightfold. Cells cultured in the presence of 10(-9)-10(-5) M dexamethasone or hydrocortisone displayed a dose-dependent increase in HER-2/neu mRNA. To determine if this effect was due to stabilization of existing HER-2/neu transcripts or to new mRNA synthesis, cells were treated with actinomycin D and cycloheximide once steady-state levels of HER-2/neu mRNA had been reached. These studies demonstrated prolongation of the half-life of existing HER-2/neu transcripts in the presence of dexamethasone. No concomitant increase in the p185HER-2/neu receptor protein in response to dexamethasone could be demonstrated by Western blot or immunohistochemical analyses. Cellular proliferation was inhibited approximately 20% by the presence of dexamethasone. These data suggest that post-transcriptional regulatory mechanisms may play a role in modulating some of the biologic effects of the HER-2/neu oncogene.
Karlan
B Y
BY
Department of Obstetrics and Gynecology, Cedars-Sinai Medical Center, Los Angeles, California.
Jones
J
J
Slamon
D J
DJ
Lagasse
L D
LD
D002455:Cell Division / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004355:Drug Stability; D004848:Epithelium / Q000473:pathology; D066246:ErbB Receptors / Q000502:physiology; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression / Q000187:drug effects; D015321:Gene Rearrangement; D006801:Humans; D007700:Kinetics; D009856:Oncogene Proteins, Viral / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases; D014407:Tumor Cells, Cultured / Q000187:drug effects
D003907:Dexamethasone; D066246:ErbB Receptors; D009856:Oncogene Proteins, Viral; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases