DNA structure-specific endonuclease FEN1 as a novel drug target in tamoxifen resistant breast cancer.

Estrogen receptor a (ERa) is a key transcriptional regulator in the majority of breast cancers. ERa-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 ERa-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1 played a causal role in ERa-driven cell growth. FEN1 impacted the transcriptional-activity of ERa by facilitating coactivator recruitment to the ERa transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERa, resulting in loss of ERa-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERa-function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex-vivo cultured ERa-positive breast tumors. Collectively, these results provide therapeutic proof-of-principle for FEN1 blockade in tamoxifen-resistant breast cancer. Overall design: RNA-seq and Chip-seq of ERa, FOXA1, XRCC1, PCNA, POLII, PARP1, XRCC1, BRG1 and FAIRE-seq in MCF-7 cells treated with siRNAs or FEN1 inhibitor RRBS of MCF-7 cells treated -+ 45 min E2 -+ FEN1 inhibitor