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

Research output: Contribution to journalArticle

  • Bruno M Simões
  • Angélica Santiago-Gómez
  • Chiara Chiodo
  • Tiago Moreira
  • Daniel Conole
  • Scott Lovell
  • Denis G Alférez
  • Rachel Eyre
  • Katherine Spence
  • Aida Sarmiento-Castro
  • Bertram Kohler
  • Ludivine Morisset
  • Marilena Lanzino
  • Sebastiano Andó
  • Elisabetta Marangoni
  • Andrew Sims
  • Edward W Tate
  • Sacha J Howell
  • Robert B. Clarke

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Original languageEnglish
JournalOncogene
Early online date30 May 2020
DOIs
Publication statusE-pub ahead of print - 30 May 2020

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 induceSTAT3 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.

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