Characterization of the Breast Cancer Susceptibility Gene BRCA2
Final rept. 16 Aug 1997-15 Aug 2000
DUKE UNIV MEDICAL CENTER DURHAM NC
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Estrogen promotes DNA synthesis in breast epithelial cells via its interaction with the estrogen receptor. The primary mode of estrogen action has been considered to be through transcriptional activation of genes containing estrogen response elements. Alternatively, estrogen may stimulate cell cycle progression by activating the MAPK cascade. Specific small molecule inhibitors of MAPK and P13-kinase activity were used to determine the influence of these cascades on estrogen-mediated mitogenesis. Inhibitors of both cascades decreased the fraction of cells entering DNA synthesis after treatment with 17 beta-estradiol. These compounds did not inhibit expression of myc or fos, but did prevent the accumulation of cyclin Dl. Interestingly, the downstream targets of these pathways were not activated over basal levels in response to hormone treatment. This suggests that estrogen initiates mitogenesis by regulating transcription, but signaling pathways may regulate subsequent events. The minimal concentrations of estrogen sufficient to induce mitogenesis or transcription were shown to be the same, implying that these two activities cannot be uncoupled. Cumulatively, these studies indicate that estrogen initiates cell cycle progression by stimulating the transcription of immediate early genes and that the action of basal levels of MAPK and P13-K are essential at, or prior to, the Gi checkpoint.
- Medicine and Medical Research