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    Anti-estrogen resistance in human breast tumors Is driven by JAG1-NOTCH4-dependent cancer stem cell activity.

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    Authors
    Simões, Bruno M
    O'Brien, Ciara S
    Eyre, Rachel
    Silva, Andreia
    Yu, Ling
    Sarmiento-Castro, Aida
    Alférez, Denis G
    Spence, Katherine
    Santiago-Gómez, Angélica
    Chemi, Francesca
    Acar, Ahmet
    Gandhi, A
    Howell, Anthony
    Brennan, K
    Rydén, L
    Catalano, S
    Andó, S
    Gee, J
    Ucar, Ahmet
    Sims, A
    Marangoni, E
    Farnie, Gillian
    Landberg, Göran
    Howell, Sacha J
    Clarke, Robert B
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    Affiliation
    Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX
    Issue Date
    2015-09-29
    
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    Abstract
    Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.
    Citation
    Anti-estrogen resistance in human breast tumors Is driven by JAG1-NOTCH4-dependent cancer stem cell activity. 2015, 12 (12):1968-77 Cell Rep
    Journal
    Cell Reports
    URI
    http://hdl.handle.net/10541/581070
    DOI
    10.1016/j.celrep.2015.08.050
    PubMed ID
    26387946
    Type
    Article
    Language
    en
    ISSN
    2211-1247
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.celrep.2015.08.050
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