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

Pasquale Sansone, Claudio Ceccarelli, Marjan Berishaj, Qing Chang, Vinagolu K. Rajasekhar, Fabiana Perna, Robert L. Bowman, Michele Vidone, Laura Daly, Jennifer Nnoli, Donatella Santini, Mario Taffurelli, Natalie N. C. Shih, Michael Feldman, Jun J. Mao, Christopher Colameco, Jinbo Chen, Angela DeMichele, Nicola Fabbri, John H. Healey, Monica Cricca, Giuseppe Gasparre, David Lyden (), Massimiliano Bonafé () and Jacqueline Bromberg ()
Additional contact information
Pasquale Sansone: Memorial Sloan Kettering Cancer Center
Claudio Ceccarelli: Diagnostic and Specialty Medicine, AlmaMater Studiorum, Universita' di Bologna
Marjan Berishaj: Memorial Sloan Kettering Cancer Center
Qing Chang: Memorial Sloan Kettering Cancer Center
Vinagolu K. Rajasekhar: Memorial Sloan Kettering Cancer Center
Fabiana Perna: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center
Robert L. Bowman: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center
Michele Vidone: AlmaMater Studiorum, Universita' di Bologna
Laura Daly: Memorial Sloan Kettering Cancer Center
Jennifer Nnoli: Memorial Sloan Kettering Cancer Center
Donatella Santini: Pathology Unit, Policlinico S.Orsola-Malpighi University Hospital
Mario Taffurelli: AlmaMater Studiorum, Universita' di Bologna
Natalie N. C. Shih: Hospital of the University of Pennsylvania
Michael Feldman: Hospital of the University of Pennsylvania
Jun J. Mao: Abramson Cancer Center, University of Pennsylvania
Christopher Colameco: Abramson Cancer Center, University of Pennsylvania
Jinbo Chen: Abramson Cancer Center, University of Pennsylvania
Angela DeMichele: Abramson Cancer Center, University of Pennsylvania
Nicola Fabbri: Orthopedics Service, Memorial Sloan Kettering Cancer Center
John H. Healey: Orthopedics Service, Memorial Sloan Kettering Cancer Center
Monica Cricca: Diagnostic and Specialty Medicine, AlmaMater Studiorum, Universita' di Bologna
Giuseppe Gasparre: AlmaMater Studiorum, Universita' di Bologna
David Lyden: Memorial Sloan Kettering Cancer Center
Massimiliano Bonafé: Diagnostic and Specialty Medicine, AlmaMater Studiorum, Universita' di Bologna
Jacqueline Bromberg: Memorial Sloan Kettering Cancer Center

Nature Communications, 2016, vol. 7, issue 1, 1-10

Abstract: Abstract The mechanisms of metastatic progression from hormonal therapy (HT) are largely unknown in luminal breast cancer. Here we demonstrate the enrichment of CD133hi/ERlo 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 CD133hi/ERlo/IL6hi cancer stem cells (CSCs). HT initially abrogates oxidative phosphorylation (OXPHOS) generating self-renewal-deficient cancer cells, CD133hi/ERlo/OXPHOSlo. These cells exit metabolic dormancy via an IL6-driven feed-forward ERlo-IL6hi-Notchhi loop, activating OXPHOS, in the absence of ER activity. The inhibition of IL6R/IL6-Notch pathways switches the self-renewal of CD133hi 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 CD133hi/ERlo cells mediating metastatic progression, which is sensitive to dual targeted therapy.

Date: 2016
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DOI: 10.1038/ncomms10442

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