title: Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.
abstract: Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Bruno M
authors.initials: BM
authors.lastname: Simões
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Ciara S
authors.initials: CS
authors.lastname: O'Brien
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Rachel
authors.initials: R
authors.lastname: Eyre
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Andreia
authors.initials: A
authors.lastname: Silva
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Ling
authors.initials: L
authors.lastname: Yu
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Aida
authors.initials: A
authors.lastname: Sarmiento-Castro
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Denis G
authors.initials: DG
authors.lastname: Alférez
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Kath
authors.initials: K
authors.lastname: Spence
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Angélica
authors.initials: A
authors.lastname: Santiago-Gómez
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Chemi
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Acar
authors.affiliation: Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Manchester M23 9LT, UK.
authors.forename: Ashu
authors.initials: A
authors.lastname: Gandhi
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.affiliation: Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Keith
authors.initials: K
authors.lastname: Brennan
authors.affiliation: Department of Surgery, Clinical Sciences, Lund University, Skåne University Hospital, 21428 Malmö, Sweden.
authors.forename: Lisa
authors.initials: L
authors.lastname: Rydén
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Catalano
authors.affiliation: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Andó
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, University of Cardiff, Cardiff, Wales CF10 3NB, UK.
authors.forename: Julia
authors.initials: J
authors.lastname: Gee
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK; Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Ahmet
authors.initials: A
authors.lastname: Ucar
authors.affiliation: Applied Bioinformatics of Cancer Group, Systems Medicine Building, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Sims
authors.affiliation: Laboratoire d'Investigation Préclinique, Institut Curie, 26 rue d'Ulm 75248 Paris Cedex 05, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Gillian
authors.initials: G
authors.lastname: Farnie
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
authors.forename: Göran
authors.initials: G
authors.lastname: Landberg
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. Electronic address: sacha.howell@christie.nhs.uk.
authors.forename: Sacha J
authors.initials: SJ
authors.lastname: Howell
authors.affiliation: Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK. Electronic address: robert.clarke@manchester.ac.uk.
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clarke
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001552:Benzazepines / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000074562:Receptor, Notch4; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D050697:Retinal Dehydrogenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D016019:Survival Analysis; D013629:Tamoxifen / Q000494:pharmacology; D000072056:Transcription Factor HES-1; D023041:Xenograft Model Antitumor Assays; D010128:p-Aminoazobenzene / Q000031:analogs & derivatives / Q000494:pharmacology; D005466:Fluorocarbons
chemical_list: D000080924:Aldehyde Dehydrogenase 1 Family; D018931:Antineoplastic Agents, Hormonal; D051792:Basic Helix-Loop-Helix Proteins; D001552:Benzazepines; D002135:Calcium-Binding Proteins; D018797:Cell Cycle Proteins; D004958:Estradiol; D065171:Estrogen Receptor Antagonists; D000077267:Fulvestrant; D018398:Homeodomain Proteins; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D011960:Receptors, Estrogen; D051880:Receptors, Notch; D050697:Retinal Dehydrogenase; D000072099:Serrate-Jagged Proteins; D013629:Tamoxifen; D000072056:Transcription Factor HES-1; D010128:p-Aminoazobenzene; C485631:HEY1 protein, human; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; C106075:NOTCH4 protein, human; C078493:HES1 protein, human; C007368:C.I. Solvent Yellow 56; C510223:ALDH1A1 protein, human; C515028:ALDH1A1 protein, mouse; C545185:2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide; D005466:Fluorocarbons