**2.5 The influence of dexamethasone on ABCG2 expression and function**

Glucocorticoides are efficacious in the reducing of chemotherapy adverse side effects and show their intrinsic anticancer activity (Vee et al., 2009) (Pavek et al., 2005). Some glucocorticoids, such as beclomethasone, 6α-methylprednisolone, dexamethasone, and triamcinolone, at micromolar concentrations, are shown to efficiently decrease the transport of ABCG2 substrates (Pavek et al., 2005).

Glucocorticoide receptor agonists regulate gene expression in various ways, at the transcriptional (Adcock, 2001), posttranscriptional (Korhonen et al., 2002), and posttranslational levels (Kritsch et al., 2002). Direct interaction of ligand-activated GR with control elements of target genes could regulate gene transcription in a positive or negative way. However, there are different mechanisms for the negative regulation of gene transcription by glucocorticoides. They could interfere with general transcription factors such as activator protein-1 (AP-1) (Herrlich, 2001) and nuclear factor-κB (NF-κB) (Almawi et al., 2002), resulting in decreased transcription of AP-1- and NF-κB -responsive genes. Genomic organization of the ABCG2 gene revealed the presence of several AP-1 sites in the ABCG2 promoter (Bailey-Dell et al., 2001). So it could be a direct target of transcriptional repression in a similar way. On the other hand, it has been reported that dexamethasone mediates negative regulation of gene expression by destabilizing the mRNA of some target genes (Garcia-Gras et al., 2000; Lasa et al., 2002).

Investigating the effects of dexamethasone on ABCG2 expression in MCF-7 cells showed that dexamethasone decreased the mRNA level of ABCG2 gene in comparison with control in MCF-7 and MCF-7/MX cell lines. Flow cytometry analysis indicated that a decrease in the level of ABCG2 protein was observed in dexamethasone treated MCF-7/MX cells. While the level of ABCG2 protein expressed as a ratio of the corresponding control was unchanged in

MCF-7 Breast Cancer Cell Line, a Model for the Study of the Association

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MCF-7 treated cells (Elahian et al., 2009). Cotreatment with different concentrations of mitoxantrone and dexamethasone increased the sensitivity of MCF-7 and MCF-7/MX cells to the toxic effects of mitoxantrone. In addition, the flow cytometry results showed that dexamethasone could inhibit the efflux and consequently caused increase in the accumulation of mitoxantrone in MCF-7/MX cells. However, ABCG2 inhibition by dexamethasone was not significant in MCF-7 cells (Elahian et al., 2010).

These studies also confirmed that suppression role of dexamethasone on ABCG2 expression in MCF-7/MX cells was more significant than MCF-7 cells. It could be a confirmation for higher level of ABCG2 in MCF-7/MX cells compared with their parental cells and also confirmed other studies that show hormonal regulation of MDR gene expression is cell type specific (Demeule et al., 1999; Imai et al., 2005).
