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Endonuclease FEN1 Coregulates ERα Activity and Provides a Novel Drug Interface in Tamoxifen-Resistant Breast Cancer.
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 J C; Zakharov, Alexey V; Wesseling, Jelle; Wessels, Lodewyk F A; Linn, Sabine C; Tilley, Wayne D; Simeonov, Anton; Ali, Simak; Zwart, Wilbert.
Afiliação
  • Flach KD; Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Periyasamy M; Oncode Institute, the Netherlands.
  • Jadhav A; Division of Gene Regulation, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Dorjsuren D; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
  • Siefert JC; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
  • Hickey TE; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
  • Opdam M; Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Patel H; Oncode Institute, the Netherlands.
  • Canisius S; Dame Roma Mitchell Cancer Research Laboratories, Adelaide Medical School, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia.
  • Wilson DM; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Donaldson Collier M; Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
  • Prekovic S; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Nieuwland M; Laboratory of Molecular Gerontology, Intramural Research Program, National Institute on Aging, NIH, Baltimore, Maryland.
  • Kluin RJC; Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Zakharov AV; Oncode Institute, the Netherlands.
  • Wesseling J; Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Wessels LFA; Oncode Institute, the Netherlands.
  • Linn SC; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Tilley WD; Genomics Core Facility, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Simeonov A; National Center for Advancing Translational Sciences, NIH, Bethesda, Maryland.
  • Ali S; Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
  • Zwart W; Oncode Institute, the Netherlands.
Cancer Res ; 80(10): 1914-1926, 2020 05 15.
Article em En | MEDLINE | ID: mdl-32193286
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Resistencia a Medicamentos Antineoplásicos / Endonucleases Flap / Receptor alfa de Estrogênio Tipo de estudo: Prognostic_studies Limite: Female / Humans Idioma: En Revista: Cancer Res Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Holanda País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias da Mama / Resistencia a Medicamentos Antineoplásicos / Endonucleases Flap / Receptor alfa de Estrogênio Tipo de estudo: Prognostic_studies Limite: Female / Humans Idioma: En Revista: Cancer Res Ano de publicação: 2020 Tipo de documento: Article País de afiliação: Holanda País de publicação: Estados Unidos