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

View ORCID ProfileBruno M. Simões, Angélica Santiago-Gómez, Chiara Chiodo, Tiago Moreira, Daniel Conole, Scott Lovell, Denis Alferez, Rachel Eyre, Katherine Spence, Aida Sarmiento-Castro, Bertram Kohler, Marilena Lanzino, Sebastiano Andò, Elisabetta Marangoni, Andrew H. Sims, View ORCID ProfileEdward Tate, Sacha J. Howell, View ORCID ProfileRobert B. Clarke
doi: https://doi.org/10.1101/2020.02.03.932194
Bruno M. Simões
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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  • ORCID record for Bruno M. Simões
  • For correspondence: bruno.simoes@manchester.ac.uk sacha.howell@christie.nhs.uk robert.clarke@manchester.ac.uk
Angélica Santiago-Gómez
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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Chiara Chiodo
2Department of Pharmacy, University of Calabria, Arcavacata di Rende, Italy
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Tiago Moreira
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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Daniel Conole
3Molecular Sciences Research Hub, Imperial College London, UK
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Scott Lovell
3Molecular Sciences Research Hub, Imperial College London, UK
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Denis Alferez
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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Rachel Eyre
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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Katherine Spence
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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Aida Sarmiento-Castro
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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Bertram Kohler
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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Marilena Lanzino
2Department of Pharmacy, University of Calabria, Arcavacata di Rende, Italy
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Sebastiano Andò
2Department of Pharmacy, University of Calabria, Arcavacata di Rende, Italy
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Elisabetta Marangoni
4Laboratoire d’investigation préclinique, Institut Curie, Paris, France
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Andrew H. Sims
5Applied Bioinformatics of Cancer Group, University of Edinburgh Cancer Research UK Centre, Edinburgh, UK
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Edward Tate
3Molecular Sciences Research Hub, Imperial College London, UK
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Sacha J. Howell
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
6Dept. of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
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  • For correspondence: bruno.simoes@manchester.ac.uk sacha.howell@christie.nhs.uk robert.clarke@manchester.ac.uk
Robert B. Clarke
1Manchester Breast Centre, Division of Cancer Sciences, Faculty of Biology, Medicine and Health University of Manchester, Manchester, UK
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  • ORCID record for Robert B. Clarke
  • For correspondence: bruno.simoes@manchester.ac.uk sacha.howell@christie.nhs.uk robert.clarke@manchester.ac.uk
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ABSTRACT

PURPOSE 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. Sulforaphane (SFN) has previously been shown to target CSCs but its mechanism of action is unclear. Here we investigate SFX-01, a stabilised formulation of SFN, for its effects on breast CSC activity in ER+ preclinical models and to study its mechanism.

EXPERIMENTAL DESIGN CSC activity was measured by mammosphere formation efficiency (MFE), aldehyde dehydrogenase (ALDH) activity, and tumor formation using patient samples and patient-derived xenograft (PDX) tumors treated with SFX-01 alone or in combination with tamoxifen or fulvestrant. Gene expression and SFN target proteins in treated samples were assessed.

RESULTS SFX-01 reduced MFE of both ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and ALDH activity of PDX tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor initiating cell frequency in secondary transplants at limiting dilution 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.

CONCLUSIONS 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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted February 04, 2020.
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Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer
Bruno M. Simões, Angélica Santiago-Gómez, Chiara Chiodo, Tiago Moreira, Daniel Conole, Scott Lovell, Denis Alferez, Rachel Eyre, Katherine Spence, Aida Sarmiento-Castro, Bertram Kohler, Marilena Lanzino, Sebastiano Andò, Elisabetta Marangoni, Andrew H. Sims, Edward Tate, Sacha J. Howell, Robert B. Clarke
bioRxiv 2020.02.03.932194; doi: https://doi.org/10.1101/2020.02.03.932194
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Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer
Bruno M. Simões, Angélica Santiago-Gómez, Chiara Chiodo, Tiago Moreira, Daniel Conole, Scott Lovell, Denis Alferez, Rachel Eyre, Katherine Spence, Aida Sarmiento-Castro, Bertram Kohler, Marilena Lanzino, Sebastiano Andò, Elisabetta Marangoni, Andrew H. Sims, Edward Tate, Sacha J. Howell, Robert B. Clarke
bioRxiv 2020.02.03.932194; doi: https://doi.org/10.1101/2020.02.03.932194

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