Glucocorticoid receptor (GR) activation has recently been implicated in the initiation of anti-apoptotic signaling pathways in epithelial cell lines grown in culture. However, the evidence that GR-mediated inhibition of
tumor cell apoptosis is the mechanism that diminishes
chemotherapy effectiveness in vivo is limited. We therefore initiated a
breast cancer xenograft study to examine whether or not pretreatment with
glucocorticoids (GCs) decreases
tumor response to
chemotherapy by inhibiting
tumor cell apoptosis. Here we report a significant decrease in
paclitaxel-induced apoptosis in xenografts from mice pretreated with
dexamethasone (Dex). A significant difference in apoptosis in xenografts from Dex/
paclitaxel versus
paclitaxel treated animals was seen eight days following initiation of
chemotherapy. Nine days later, mice treated with Dex/
paclitaxel had significantly larger
tumors compared with those that received
paclitaxel alone (p = 0.032). Dex pretreatment did not significantly affect
tumor cell proliferation rates. Taken together, these results demonstrate that systemic Dex administration results in significantly reduced
breast cancer xenograft apoptosis in the context of
chemotherapy treatment. We also found that systemic Dex treatment results in upregulation of the anti-apoptotic gene MKP-1 and downregulation of pro-apoptotic Bid and TRAIL genes in
tumor cells six hours following Dex treatment. These in vivo gene expression changes correlated with significant inhibition of
chemotherapy-induced apoptosis. Interestingly, the decreased chemotherapeutic response of Dex-pretreated
tumors persisted for several weeks following treatment. These data suggest that GR-mediated transcriptional regulation of pro- and anti-apoptotic genes contributes to the mechanism through which GCs decrease
paclitaxel-induced apoptosis.