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    Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

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    Authors
    Simoes, Bruno M
    Santiago-Gómez, Angélica
    Chiodo, Chiara
    Moreira, Tiago
    Conole, D.
    Lovell, S.
    Alférez, Denis G
    Eyre, Rachel
    Spence, Katherine
    Sarmiento-Castro, Aida
    Kohler, Bertram
    Morisset, L.
    Lanzino, M.
    Ando, S.
    Marangoni, E.
    Sims, A. H.
    Tate, E. W.
    Howell, Sacha J
    Clarke, Robert B
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    Affiliation
    Breast Biology Group, Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester
    Issue Date
    2020
    
    Metadata
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    Abstract
    Estrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Here we investigate SFX-01, a stabilised formulation of sulforaphane (SFN), for its effects on breast CSC activity in ER+ preclinical models. SFX-01 reduced mammosphere formation efficiency (MFE) of ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and aldehyde dehydrogenase (ALDH) activity of patient-derived xenograft (PDX) tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor-initiating cell frequency in secondary transplants and reduced the formation of spontaneous lung micrometastases by PDX tumors in mice. Mechanistically, we establish that both tamoxifen and fulvestrant induce STAT3 phosphorylation. SFX-01 suppressed phospho-STAT3 and SFN directly bound STAT3 in patient and PDX samples. Analysis of ALDH+ cells from endocrine-resistant patient samples revealed activation of STAT3 target genes MUC1 and OSMR, which were inhibited by SFX-01 in patient samples. Increased expression of these genes after 3 months' endocrine treatment of ER+ patients (n = 68) predicted poor prognosis. Our data establish the importance of STAT3 signaling in CSC-mediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.
    Citation
    B. M. Simoes, A. Santiago-Gomez, C. Chiodo et al Targeting STAT3 signaling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer. Oncogene. 2020.
    Journal
    Oncogene
    URI
    http://hdl.handle.net/10541/623008
    DOI
    10.1038/s41388-020-1335-z
    PubMed ID
    32472077
    Additional Links
    https://dx.doi.org/10.1038/s41388-020-1335-z
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41388-020-1335-z
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