title: Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer.
abstract: 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.
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Pasquale
authors: P
authors: Sansone
authors: Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Universita' di Bologna, Bologna 40138, Italy.
authors: Claudio
authors: C
authors: Ceccarelli
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Marjan
authors: M
authors: Berishaj
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Qing
authors: Q
authors: Chang
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Vinagolu K
authors: VK
authors: Rajasekhar
authors: Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Fabiana
authors: F
authors: Perna
authors: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Robert L
authors: RL
authors: Bowman
authors: Department of Medical and Surgical Sciences, AlmaMater Studiorum, Universita' di Bologna, Bologna 40138, Italy.
authors: Michele
authors: M
authors: Vidone
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Laura
authors: L
authors: Daly
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Jennifer
authors: J
authors: Nnoli
authors: Pathology Unit, Policlinico S.Orsola-Malpighi University Hospital, Bologna 40138, Italy.
authors: Donatella
authors: D
authors: Santini
authors: Department of Medical and Surgical Sciences, AlmaMater Studiorum, Universita' di Bologna, Bologna 40138, Italy.
authors: Mario
authors: M
authors: Taffurelli
authors: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Natalie N C
authors: NN
authors: Shih
authors: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Michael
authors: M
authors: Feldman
authors: Department of Biostatistics and Epidemiology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Jun J
authors: JJ
authors: Mao
authors: Department of Biostatistics and Epidemiology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Christopher
authors: C
authors: Colameco
authors: Department of Biostatistics and Epidemiology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Jinbo
authors: J
authors: Chen
authors: Department of Biostatistics and Epidemiology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.|Department of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors: Angela
authors: A
authors: DeMichele
authors: Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: Nicola
authors: N
authors: Fabbri
authors: Orthopedics Service, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.
authors: John H
authors: JH
authors: Healey
authors: Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Universita' di Bologna, Bologna 40138, Italy.
authors: Monica
authors: M
authors: Cricca
authors: Department of Medical and Surgical Sciences, AlmaMater Studiorum, Universita' di Bologna, Bologna 40138, Italy.
authors: Giuseppe
authors: G
authors: Gasparre
authors: Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.|Department of Pediatrics, Cell and Developmental Biology, Children's Cancer and Blood Foundation Laboratories, Weill Cornell Medical College, New York, New York 10021, USA.
authors: David
authors: D
authors: Lyden
authors: Department of Experimental, Diagnostic and Specialty Medicine, AlmaMater Studiorum, Universita' di Bologna, Bologna 40138, Italy.|CRBA Laboratory, Policlinico Universitario S. Orsola-Malpighi, Bologna 40138, Italy.
authors: Massimiliano
authors: M
authors: Bonafé
authors: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA.|Department of Medicine, Weill Cornell Medical College, New York, New York 10021, USA.
authors: Jacqueline
authors: J
authors: Bromberg
mesh_terms: D000071916:AC133 Antigen; D000077384:Anastrozole; D000730:Androstadienes; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal; D001859:Bone Neoplasms / Q000235:genetics* / Q000556:secondary; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000235:genetics* / Q000556:secondary; D018275:Carcinoma, Lobular / Q000235:genetics* / Q000556:secondary; D045744:Cell Line, Tumor; D000066673:Cell Self Renewal / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004958:Estradiol / Q000031:analogs & derivatives; D005260:Female; D005434:Flow Cytometry; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D015850:Interleukin-6 / Q000235:genetics; D000077289:Letrozole; D016729:Leuprolide; D061986:MCF-7 Cells; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D009570:Nitriles; D010085:Oxidative Phosphorylation; D010455:Peptides / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D000071656:Receptor, Notch3; D011960:Receptors, Estrogen / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D013629:Tamoxifen; D014230:Triazoles
chemical_list: D000071916:AC133 Antigen; D000730:Androstadienes; D015703:Antigens, CD; D018931:Antineoplastic Agents, Hormonal; D006023:Glycoproteins; D015850:Interleukin-6; C499374:NOTCH3 protein, human; D009570:Nitriles; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D000071656:Receptor, Notch3; D011960:Receptors, Estrogen; D051880:Receptors, Notch; D014230:Triazoles; D013629:Tamoxifen; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol; D000077289:Letrozole; D016729:Leuprolide; C056516:exemestane