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https://hdl.handle.net/2440/126182
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Type: | Journal article |
Title: | Endonuclease FEN1 coregulates ERα activity and provides a novel drug interface in tamoxifen resistant breast cancer |
Author: | Flach, K.D. Periyasamy, M. Jadhav, A. Dorjsuren, D. Siefert, J.C. Hickey, T.E. Opdam, M. Patel, H. Canisius, S. Wilson, D.M. Donaldson Collier, M. Prekovic, S. Nieuwland, M. Kluin, R.J. Zakharov, A.V. Wesseling, J. Wessels, L.F.A. Linn, S.C. Tilley, W.D. Simeonov, A. et al. |
Citation: | Cancer Research, 2020; 80(10):1914-1926 |
Publisher: | American Association for Cancer Research |
Issue Date: | 2020 |
ISSN: | 0008-5472 1538-7445 |
Statement of Responsibility: | Koen D. Flach, Manikandan Periyasamy, Ajit Jadhav, Dorjbal Dorjsuren, Joseph C. Siefert ... Wayne D. Tilley ... et al. |
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. |
Keywords: | Cell Line, Tumor Humans Breast Neoplasms Tamoxifen Flap Endonucleases Estrogen Receptor alpha Antineoplastic Agents, Hormonal Gene Expression Regulation, Neoplastic Drug Resistance, Neoplasm Female |
Rights: | © 2020 American Association for Cancer Research. |
DOI: | 10.1158/0008-5472.CAN-19-2207 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1084416 http://purl.org/au-research/grants/nhmrc/20160711 |
Published version: | http://dx.doi.org/10.1158/0008-5472.can-19-2207 |
Appears in Collections: | Aurora harvest 8 Medicine publications |
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