Cell Reports (Sep 2015)
Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity
- Bruno M. Simões,
- Ciara S. O’Brien,
- Rachel Eyre,
- Andreia Silva,
- Ling Yu,
- Aida Sarmiento-Castro,
- Denis G. Alférez,
- Kath Spence,
- Angélica Santiago-Gómez,
- Francesca Chemi,
- Ahmet Acar,
- Ashu Gandhi,
- Anthony Howell,
- Keith Brennan,
- Lisa Rydén,
- Stefania Catalano,
- Sebastiano Andó,
- Julia Gee,
- Ahmet Ucar,
- Andrew H. Sims,
- Elisabetta Marangoni,
- Gillian Farnie,
- Göran Landberg,
- Sacha J. Howell,
- Robert B. Clarke
Affiliations
- Bruno M. Simões
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Ciara S. O’Brien
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Rachel Eyre
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Andreia Silva
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Ling Yu
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Aida Sarmiento-Castro
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Denis G. Alférez
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Kath Spence
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Angélica Santiago-Gómez
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Francesca Chemi
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Ahmet Acar
- Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK
- Ashu Gandhi
- Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Manchester M23 9LT, UK
- Anthony Howell
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Keith Brennan
- Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK
- Lisa Rydén
- Department of Surgery, Clinical Sciences, Lund University, Skåne University Hospital, 21428 Malmö, Sweden
- Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
- Sebastiano Andó
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
- Julia Gee
- Cardiff School of Pharmacy and Pharmaceutical Sciences, University of Cardiff, Cardiff, Wales CF10 3NB, UK
- Ahmet Ucar
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Andrew H. Sims
- Applied Bioinformatics of Cancer Group, Systems Medicine Building, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK
- Elisabetta Marangoni
- Laboratoire d’Investigation Préclinique, Institut Curie, 26 rue d’Ulm 75248 Paris Cedex 05, France
- Gillian Farnie
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Göran Landberg
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Sacha J. Howell
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- Robert B. Clarke
- Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK
- DOI
- https://doi.org/10.1016/j.celrep.2015.08.050
- Journal volume & issue
-
Vol. 12,
no. 12
pp. 1968 – 1977
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.