Inhibition of mouse skin tumorigenesis by dexamethasone occurs through a Ha-ras-independent mechanism.
The Ha-ras oncogene has been shown to be point-mutated and overexpressed in papillomas induced by the two-stage skin tumorigenesis regimen of 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). Glucocorticoids inhibit mouse skin tumorigenesis when applied with the initiation agent or with the promoting agent. We have extended these studies to evaluate whether dexamethasone (Dex) treatment could inhibit development of already established tumors. An additional objective of this study was to investigate whether glucocorticoids directly inhibit Ha-ras gene expression at the level of transcription during skin tumorigenesis. In this report we demonstrate that topical Dex treatments significantly suppressed the formation of additional tumors relative to the acetone control group. However, Northern blot analysis of total RNA isolated from representative tumors during a series of sequential weeks of promotion indicated that Dex did not have a direct effect on Ha-ras steady-state mRNA levels despite the decrease in additional tumor numbers in the Dex-treated groups. We also investigated short-term effects of Dex on endogenous Ha-ras expression in normal mouse epidermis. Topical Dex administration had no effect on endogenous Ha-ras steady-state mRNA levels in normal skin after 2 or 24 h. To ensure that endogenous corticosterone levels in the SENCAR mouse were not influencing our results, Ha-ras mRNA levels in epidermis from SENCAR mice adrenalectomized 48 h prior to being killed were compared to Ha-ras levels in normal epidermis by Northern blot analysis. The data from this analysis revealed that bilateral adrenalectomy had no effect on Ha-ras steady-state mRNA levels in epidermis compared to ras levels in normal mouse epidermis. In summary, our results demonstrate that although Dex can inhibit further tumor development in DMBA/TPA-treated mouse epidermis, it does not do so by directly effecting Ha-ras gene expression in mouse epidermis.
Strawhecker
J M
JM
Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198.
Pelling
J C
JC
D015127:9,10-Dimethyl-1,2-benzanthracene; D000315:Adrenalectomy; D000818:Animals; D015152:Blotting, Northern; D003907:Dexamethasone / Q000627:therapeutic use*; D005260:Female; D011905:Genes, ras; D051379:Mice; D010212:Papilloma / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics; D013755:Tetradecanoylphorbol Acetate
D012333:RNA, Messenger; D015127:9,10-Dimethyl-1,2-benzanthracene; D003907:Dexamethasone; D013755:Tetradecanoylphorbol Acetate