Endonuclease FEN1 coregulates ERα activity and provides a novel drug interface in tamoxifen resistant breast cancer.

Abstract

Estrogen receptor α (ERα) is a key transcriptional regulator in the majority of breast cancers. ERα-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 ERα-positive patient prognostication. FEN1 levels were predictive of outcome in tamoxifen-treated patients, and FEN1played a causal role in ERα-driven cell growth. FEN1 impacted the transcriptional-activity of ERα by facilitating coactivator recruitment to the ERα transcriptional complex. FEN1 blockade induced proteasome-mediated degradation of activated ERα, resulting in loss of ERα-driven gene expression and eradicated tumor cell proliferation. Finally, a high-throughput 465,195 compound screen identified a novel FEN1 inhibitor, which effectively blocked ERα-function and inhibited proliferation of tamoxifen-resistant cell lines as well as ex-vivo cultured ERα-positive breast tumors. Collectively, these results provide therapeutic proof-of-principle for FEN1 blockade in tamoxifen-resistant breast cancer.

Authors

Flach, Koen D; Periyasamy, Manikandan; Jadhav, Ajit; Dorjsuren, Dorjbal; Siefert, Joseph C; Hickey, Theresa E; Opdam, Mark; Patel, Hetal; Canisius, Sander; Wilson, David M; Donaldson Collier, Maria; Prekovic, Stefan; Nieuwland, Marja; Kluin, Roelof Jc; Zakharov, Alexey; Wesseling, Jelle; Wessels, Lodewyk F A; Linn, Sabine C; Tilley, Wayne D; Simeonov, Anton; Ali, Simak; Zwart, Wilbert;

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