The antiviral drug telaprevir induces cell death by reducing FOXA1 expression in estrogen receptor α (ERα)-positive breast cancer cells

Previously, we found that telaprevir (Tel), the inhibitor of hepatitis C virus NS3/4A serine protease, reduces estrogen receptor alpha (ER alpha) content at the transcriptional level without binding to the receptor, prevents ER alpha transcriptional activity, and inhibits basal and 17 beta-estradiol (E2)-dependent cell proliferation in different breast cancer (BC) cell lines. Here, we further characterize the Tel action mechanisms on ER alpha levels and function, identify a possible molecular target of Tel in BC cells, and evaluate Tel as an antiproliferative agent for BC treatment. Tel-dependent reduction in ER alpha levels and function depends on a Tel-dependent decrease in FOXA1 levels and activity. The effect of Tel is transduced by the IGF1-R/AKT/FOXA1 pathway, with the antiviral compound interacting with IGF1-R. Tel prevents the proliferation of several BC cell lines, while it does not affect the proliferation of normal nontransformed cell lines, and its antiproliferative effect is correlated with the ratio of FOXA1/IGF1-R expression. In conclusion, Tel interferes with the IGF1-R/AKT/FOXA1 pathway and induces cell death in ER alpha-expressing BC cells. Thus, we propose that this antiviral could be repurposed for the treatment of ER alpha-expressing BC.

Automated summary

Telaprevir reduces the levels and function of estrogen receptor alpha (ER alpha) by decreasing FOXA1 levels and activity. The antiviral compound interacts with IGF1-R and transduces its effect through the IGF1-R/AKT/FOXA1 pathway, resulting in cell death in ER alpha-expressing breast cancer cells.