Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.

TitleSelf-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsSansone P, Ceccarelli C, Berishaj M, Chang Q, Rajasekhar VK, Perna F, Bowman RL, Vidone M, Daly LA, Nnoli J, Santini D, Taffurelli M, Shih NNC, Feldman M, Mao JJ, Colameco C, Chen J, DeMichele A, Fabbri N, Healey JH, Cricca M, Gasparre G, Lyden DC, Bonafé M, Bromberg JF
JournalNat Commun
Date Published2016 Feb 09
KeywordsAC133 Antigen, Anastrozole, Androstadienes, Animals, Antigens, CD, Antineoplastic Agents, Hormonal, Bone Neoplasms, Breast Neoplasms, Carcinoma, Ductal, Breast, Carcinoma, Lobular, Cell Line, Tumor, Cell Self Renewal, Drug Resistance, Neoplasm, Estradiol, Female, Flow Cytometry, Fulvestrant, Gene Expression Regulation, Neoplastic, Glycoproteins, Humans, In Vitro Techniques, Interleukin-6, Letrozole, Leuprolide, MCF-7 Cells, Mice, Inbred NOD, Mice, SCID, Neoplasm Metastasis, Neoplasm Transplantation, Neoplastic Stem Cells, Nitriles, Oxidative Phosphorylation, Peptides, Real-Time Polymerase Chain Reaction, Receptor, Notch3, Receptors, Estrogen, Receptors, Notch, Signal Transduction, Tamoxifen, Triazoles

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.

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Alternate JournalNat Commun
PubMed ID26858125
PubMed Central IDPMC4748123
Grant ListR01 CA87637 / CA / NCI NIH HHS / United States
U01-CA169538 / CA / NCI NIH HHS / United States
R01 CA158243 / CA / NCI NIH HHS / United States
P30 CA008748 / CA / NCI NIH HHS / United States
R01 CA087637 / CA / NCI NIH HHS / United States
U01 CA169538 / CA / NCI NIH HHS / United States
P30 CA016520 / CA / NCI NIH HHS / United States

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