Endonuclease FEN1 Coregulates ERα Activity and Provides a Novel Drug Interface in Tamoxifen-Resistant Breast Cancer

Abstract

Estrogen receptor alpha (ER alpha) is a key transcriptional regulator in the majority of breast cancers. ER alpha-positive patients are frequently treated with tamoxifen, but resistance is common. In this study, we refined a previously identified 111-gene outcome prediction-classifier, revealing FEN1 as the strongest determining factor in ER alpha-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ER alpha-driven cell growth. FEN1 impacted the transcriptional activity of ER alpha by facilitating coactivator recruitment to the ER alpha transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ER alpha, resulting in loss of ER alpha-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ER alpha function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex vivo-cultured ER alpha-positive breast tumors. Collectively, these results provide therapeutic proof of principle for FEN1 blockade in tamoxifen-resistant breast cancer. Significance: These findings show that pharmacologic inhibition of FEN1, which is predictive of outcome in tamoxifen-treated patients, effectively blocks ER alpha function and inhibits proliferation of tamoxifen-resistant tumor cells.