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Cell Rep. 2015 Sep 29;12(12):1968-77. doi: 10.1016/j.celrep.2015.08.050. Epub 2015 Sep 17.

Anti-estrogen Resistance in Human Breast Tumors Is Driven by JAG1-NOTCH4-Dependent Cancer Stem Cell Activity.

Author information

1
Breast Cancer Now Research Unit, Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK.
2
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.
3
Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
4
Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Manchester M23 9LT, UK.
5
Department of Surgery, Clinical Sciences, Lund University, Skåne University Hospital, 21428 Malmö, Sweden.
6
Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Arcavacata di Rende, Cosenza, Italy.
7
Cardiff School of Pharmacy and Pharmaceutical Sciences, University of Cardiff, Cardiff, Wales CF10 3NB, UK.
8
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.
9
Applied Bioinformatics of Cancer Group, Systems Medicine Building, Western General Hospital, University of Edinburgh, Edinburgh EH4 2XU, UK.
10
Laboratoire d'Investigation Préclinique, Institut Curie, 26 rue d'Ulm 75248 Paris Cedex 05, France.
11
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.
12
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.

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.

PMID:
26387946
PMCID:
PMC4594158
DOI:
10.1016/j.celrep.2015.08.050
[Indexed for MEDLINE]
Free PMC Article

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