NuclearReceptors2018 Invited Speaker (1) (14 abstracts)
Estrogen receptor cistromics in breast tumors: from biomarkers to novel drug targets
Koen Dorus Flach 1 , Manikandan Periyasamy 2 , Ajit Jadhav 3 , Theresa E Hickey 4 , Mark Opdam 5 , Hetal Patel 2 , Sander Canisius 6 , David M Wilson 7 , Dorjbal Dorjsuren 3 , Marja Nieuwland 8 , Roel Kluin 8 , Alexey V Zakharov 3 , Jelle Wesseling 5 , Lodewyk Frederik Ary Wessels 6 , Sabine Charlotte Linn 5 , Wayne D Tilley 4 , Anton Simeonov 3 , Simak Ali 2 & Wilbert Zwart 1
1Department of Oncogenomics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; 2Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, UK; 3National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, MSC 3370, Maryland 20892, USA; 4Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, Faculty of Health Sciences, DX Number 650 801, University of Adelaide, Adelaide, South Australia 5005, Australia; 5Department of Molecular Pathology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; 6Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands; 7Laboratory of Molecular Gerontology, Intramural Research Program, National Institute on Aging, National Institutes of Health, Bayview Blvd 251, Baltimore, Maryland 21224, USA; 8Genomics Core Facility, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
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. Through ChIP-seq analyses, we presviously identified direct target genes of ERα acting in complex with SRC1, SRC2 or SRC3 (Zwart et al., 2011 EMBO J). Only the 111 genes there were under direct control of ERα in conjunction with SRC3 (but not the other two p160s) predicted patient outcome. Here, the 111-gene outcome prediction-classifier was further refined, revealing FEN1 as strongest determining factor in ERα-positive prognostication. We demonstrate FEN1 levels are predictive of outcome in tamoxifen-treated patients, and show FEN1 is required and sufficient for tamoxifen-resistance in ERα-positive cell lines. We show FEN1 dictates the transcriptional-activity of ERα by facilitating the formation and repair of hormone-induced DNA damage, ultimately resulting in DNA methylation changes. 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 460.000 compound screen identified a novel FEN1 inhibitor, which effectively blocks ERα-function and inhibits proliferation of tamoxifen-resistant cell lines as well as ex-vivo cultured ERα-positive breast tumors, providing therapeutic proof-of-principle for FEN1 blockade in tamoxifen-resistant breast cancer.
DOI: 10.1530/endoabs.54.IS4
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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