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 | 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 |
| Journal | Cell reports
(Cell Rep)
Vol. 12
Issue 12
Pg. 1968-77
(Sep 29 2015)
ISSN: 2211-1247 [Electronic] United States |
| PMID | 26387946
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Copyright | Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. |
| Chemical References |
- Antineoplastic Agents, Hormonal
- Basic Helix-Loop-Helix Transcription Factors
- Benzazepines
- Calcium-Binding Proteins
- Cell Cycle Proteins
- Estrogen Receptor Antagonists
- HEY1 protein, human
- Homeodomain Proteins
- Intercellular Signaling Peptides and Proteins
- Isoenzymes
- JAG1 protein, human
- Jag1 protein, mouse
- Jagged-1 Protein
- Membrane Proteins
- NOTCH4 protein, human
- Proto-Oncogene Proteins
- Receptor, Notch4
- Receptors, Estrogen
- Receptors, Notch
- Serrate-Jagged Proteins
- Transcription Factor HES-1
- Tamoxifen
- HES1 protein, human
- Fulvestrant
- C.I. Solvent Yellow 56
- Estradiol
- p-Aminoazobenzene
- Aldehyde Dehydrogenase 1 Family
- ALDH1A1 protein, human
- ALDH1A1 protein, mouse
- Retinal Dehydrogenase
- 2,2-dimethyl-N-(6-oxo-6,7-dihydro-5H-dibenzo(b,d)azepin-7-yl)-N'-(2,2,3,3,3-pentafluoropropyl)malonamide
|
| Topics |
- Aldehyde Dehydrogenase 1 Family
- Animals
- Antineoplastic Agents, Hormonal
(pharmacology)
- Basic Helix-Loop-Helix Transcription Factors
(antagonists & inhibitors, genetics, metabolism)
- Benzazepines
(pharmacology)
- Breast Neoplasms
(drug therapy, genetics, mortality, pathology)
- Calcium-Binding Proteins
(genetics, metabolism)
- Cell Cycle Proteins
(antagonists & inhibitors, genetics, metabolism)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Drug Resistance, Neoplasm
(drug effects, genetics)
- Estradiol
(analogs & derivatives, pharmacology)
- Estrogen Receptor Antagonists
(pharmacology)
- Female
- Fulvestrant
- Gene Expression Regulation, Neoplastic
- Homeodomain Proteins
(antagonists & inhibitors, genetics, metabolism)
- Humans
- Intercellular Signaling Peptides and Proteins
(genetics, metabolism)
- Isoenzymes
(antagonists & inhibitors, genetics, metabolism)
- Jagged-1 Protein
- Membrane Proteins
(genetics, metabolism)
- Mice
- Neoplastic Stem Cells
(drug effects, metabolism, pathology)
- Proto-Oncogene Proteins
(antagonists & inhibitors, genetics, metabolism)
- Receptor, Notch4
- Receptors, Estrogen
(genetics, metabolism)
- Receptors, Notch
(antagonists & inhibitors, genetics, metabolism)
- Retinal Dehydrogenase
(antagonists & inhibitors, genetics, metabolism)
- Serrate-Jagged Proteins
- Signal Transduction
- Survival Analysis
- Tamoxifen
(pharmacology)
- Transcription Factor HES-1
- Xenograft Model Antitumor Assays
- p-Aminoazobenzene
(analogs & derivatives, pharmacology)
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