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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
    Simões, Bruno M.; orcid: 0000-0003-1253-6657; email: bruno.simoes@manchester.ac.uk
    Santiago-Gómez, Angélica
    Chiodo, Chiara
    Moreira, Tiago
    Conole, Daniel; orcid: 0000-0002-3389-8377
    Lovell, Scott
    Alferez, Denis
    Eyre, Rachel
    Spence, Katherine
    Sarmiento-Castro, Aida
    Kohler, Bertram
    Morisset, Ludivine
    Lanzino, Marilena
    Andò, Sebastiano
    Marangoni, Elisabetta
    Sims, Andrew H.; orcid: 0000-0001-9082-3665
    Tate, Edward W.; orcid: 0000-0003-2213-5814
    Howell, Sacha J.; orcid: 0000-0001-8141-6515; email: sacha.howell@christie.nhs.uk
    Clarke, Robert B.; orcid: 0000-0001-5407-3123; email: robert.clarke@manchester.ac.uk
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    Publication Date
    2020-05-30
    Submitted date
    2020-02-21
    
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    Abstract
    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
    Oncogene, volume 39, issue 25, page 4896-4908
    Publisher
    Nature Publishing Group UK
    URI
    http://hdl.handle.net/10034/624767
    Type
    article
    Description
    From Springer Nature via Jisc Publications Router
    History: received 2020-02-21, rev-recd 2020-05-13, accepted 2020-05-15, registration 2020-05-16, pub-electronic 2020-05-30, online 2020-05-30, pub-print 2020-06-18
    Publication status: Published
    Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272; Grant(s): IS-BRC-1215-20007, IS-BRC-1215-20007, IS-BRC-1215-20007
    Funder: Breast Cancer Now; doi: https://doi.org/10.13039/501100007913; Grant(s): MAN-Q2
    Funder: National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs); doi: https://doi.org/10.13039/501100000849; Grant(s): NC/T001267/1
    Funder: RCUK | Medical Research Council (MRC); doi: https://doi.org/10.13039/501100000265; Grant(s): MR/K501311/1
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