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

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

Research output: Contribution to journalArticleAcademicpeer-review

5 Citations (Scopus)

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 FEN1 played 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. SIGNIFICANCE: These findings show that pharmacologic inhibition of FEN1, which is predictive of outcome in tamoxifen-treated patients, effectively blocks ERα function and inhibits proliferation of tamoxifen-resistant tumor cells.

Original languageEnglish
Pages (from-to)1914-1926
Number of pages13
JournalCancer Research
Volume80
Issue number10
DOIs
Publication statusPublished - 15 May 2020

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