Endoxifen and fulvestrant regulate gene expression of estrogen receptor alpha and its co-activators DEADbox5 and 17

Background: Application of anti-estrogens remains a standard therapy in ERα -positive breast cancer. Endoxifen acts as a selective receptor down-modulator of ERα function, while fulvestrant acts as a selective receptor down-regulator via an increased ERα inhibition and degradation. RNA helicases p68 (DDX5) and p72 (DDX17) act as co-activators of ERα. DDX17 expression correlates with decreased Her2/neu levels, extended relapse-free periods, and an increase in overall survival rates. In contrast, DDX5 expression is associated with increased Her2/neu levels and higher tumor grading, but not correlated with relapse-free or overall survival. This study aimed for the investigation of potential regulatory effects of the anti-estrogens on the expression of ERα, DDX5 and 17.

Methods: In vitro application of endoxifen and fulvestrant.

Results: Both drugs created a significant decrease of mRNA and protein expression levels of all target genes. DDX5 and 17 expression levels generally decreased, whereat endoxifen treatment triggered a stronger effect than fulvestrant. While both ERα antagonists caused a uniform decrease in ERα protein levels, DDX protein levels were differentially affected. Fulvestrant triggered a uniform downregulation of DDX5 and 17. In contrast, endoxifen stimulation resulted in an up-regulation of DDX5 and 17 protein.

Conclusion: Both ERα antagonists show regulatory effects on ERα, DDX5 and 17 expression. The in vitro data might explain individual therapeutic efficacy or the occurrence of resistance against endocrine therapy dependent on cellular context. The elucidation of DDX status might serve as a useful prognostic tool to estimate efficacy of anti-estrogen treatment in breast cancer therapy.