Self-renewal of CD133hi cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer Academic Article uri icon


MeSH Major

  • Antineoplastic Agents, Hormonal
  • Bone Neoplasms
  • Breast Neoplasms
  • Carcinoma, Ductal, Breast
  • Carcinoma, Lobular
  • Cell Self Renewal
  • Drug Resistance, Neoplasm
  • Gene Expression Regulation, Neoplastic
  • Neoplastic Stem Cells


  • The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133(hi)/ER(lo) cancer cells in clinical specimens following neoadjuvant endocrine therapy and in HT refractory metastatic disease. We develop experimental models of metastatic luminal breast cancer and demonstrate that HT can promote the generation of HT-resistant, self-renewing CD133(hi)/ER(lo)/IL6(hi) cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133(hi)/ER(lo)/OXPHOS(lo). These cells exit metabolic dormancy via an IL6-driven feed-forward ER(lo)-IL6(hi)-Notch(hi) loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133(hi) CSCs, from an IL6/Notch-dependent one to an ER-dependent one, through the re-expression of ER. Thus, HT induces an OXPHOS metabolic editing of luminal breast cancers, paradoxically establishing HT-driven self-renewal of dormant CD133(hi)/ER(lo) cells mediating metastatic progression, which is sensitive to dual targeted therapy.

publication date

  • February 9, 2016



  • Academic Article



  • eng

PubMed Central ID

  • PMC4748123

Digital Object Identifier (DOI)

  • 10.1038/ncomms10442

PubMed ID

  • 26858125

Additional Document Info

start page

  • 10442


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