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Title: | Endonuclease FEN1 Coregulates ERα Activity and Provides a Novel Drug Interface 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 Collier, Maria Donaldson Prekovic, Stefan Nieuwland, Marja Kluin, Roelof J. C. Zakharov, Alexey, V Wesseling, Jelle Wessels, Lodewyk F. A. Linn, Sabine C. Tilley, Wayne D. Simeonov, Anton Ali, Simak Zwart, Wilbert |
Issue Date: | 2020 | Publisher: | AMER ASSOC CANCER RESEARCH | Source: | CANCER RESEARCH, 80 (10) , p. 1914 -1926 | 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. | Notes: | Zwart, W (corresponding author), Netherlands Canc Inst, Div Oncogen, Amsterdam, Netherlands.; Zwart, W (corresponding author), Netherlands Canc Inst, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. w.zwart@nki.nl |
Other: | Zwart, W (corresponding author), Netherlands Canc Inst, Div Oncogen, Amsterdam, Netherlands; Netherlands Canc Inst, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands. w.zwart@nki.nl | Keywords: | Estrogen-Receptor-Alpha;Flap Endonuclease-1;Gene-Expression;Antiestrogens;Progression;Activation;Mechanisms;Inhibitors;Stability;Reveals | Document URI: | http://hdl.handle.net/1942/31556 | ISSN: | 0008-5472 | e-ISSN: | 1538-7445 | DOI: | 10.1158/0008-5472.CAN-19-2207 | ISI #: | WOS:000535265800009 | Rights: | 2020 by the American Association for Cancer Research. | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2021 |
Appears in Collections: | Research publications |
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File | Description | Size | Format | |
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WILSON_David_FigS2.pdf | Peer-reviewed author version | 133.25 kB | Adobe PDF | View/Open |
WILSON_David_CAN192207ATR1_Article_File.pdf | Peer-reviewed author version | 617.58 kB | Adobe PDF | View/Open |
WILSON_David_FigS5.pdf | Peer-reviewed author version | 99.72 kB | Adobe PDF | View/Open |
WILSON_David_Fig4.pdf | Peer-reviewed author version | 1.11 MB | Adobe PDF | View/Open |
WILSON_David_FigS4.pdf | Peer-reviewed author version | 1.16 MB | Adobe PDF | View/Open |
WILSON_David_SupplementaryMaterial.pdf | Peer-reviewed author version | 385.44 kB | Adobe PDF | View/Open |
WILSON_David_Fig2.pdf | Peer-reviewed author version | 540.54 kB | Adobe PDF | View/Open |
WILSON_David_FS3.pdf | Peer-reviewed author version | 75.57 kB | Adobe PDF | View/Open |
WILSON_David_Fig1.pdf | Peer-reviewed author version | 756.1 kB | Adobe PDF | View/Open |
WILSON_David_Fig3.pdf | Peer-reviewed author version | 1.09 MB | Adobe PDF | View/Open |
WILSON_David_Fig5.pdf | Peer-reviewed author version | 775.41 kB | Adobe PDF | View/Open |
WILSON_David_FigS1.pdf | Peer-reviewed author version | 139.78 kB | Adobe PDF | View/Open |
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