New approach found to tackle breast cancer hormone therapy resistance

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New approach found to tackle breast cancer hormone therapy resistance

Monday, 28.09.2015

Around 75% of breast cancers are estrogen receptor-positive (ER+) and are treated with anti-estrogen therapies, such as tamoxifen. But around one in four of these cases recur, which is why it’s so important that we continue to learn more about how the disease finds ways to survive in some patients and not others.

We found that cancer stem cells survive anti-estrogen treatments by activating Notch signaling. We then showed that combining standard anti-estrogen therapies with a Notch pathway inhibitor could improve treatment of ER+ breast cancer patients by preventing relapse due to therapy resistance.

 

Authors and Affiliations:

Bruno M. Simões1, Ciara S. O’Brien1, Rachel Eyre1, Andreia Silva1, Ling Yu1, Aida Sarmiento-Castro1, Denis Alferez1, Kath Spence1, Angélica Santiago-Gómez1, Francesca Chemi1,2, Ahmet Acar3, Ashu Gandhi4, Anthony Howell1, Keith Brennan3, Lisa Rydén5, Stefania Catalano2, Sebastiano Andó2, Julia Gee6, Ahmet Ucar1,3, Andrew H. Sims7, Elisabetta Marangoni8, Gillian Farnie1, Göran Landberg1, Sacha Howell1 and Robert B. Clarke1

1 Breast Cancer Now Research Unit and Institute of Cancer Sciences, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK

2Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Cosenza, Italy

3 Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester, M13 9PT, UK

4 University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Southmoor Road, Manchester, M23 9LT, UK

5 Surgery, Department of Clinical Sciences Malmö, Lund University, Skåne University Hospital, Malmö, Sweden.

6Cardiff School of Pharmacy and Pharmaceutical Sciences, University of Cardiff, Cardiff, Wales, CF10 3NB, UK

 7Applied Bioinformatics of Cancer Group, University of Edinburgh, Systems Medicine Building, Western General Hospital, Edinburgh, UK

8Laboratoire d'investigation préclinique, Institut Curie, 26 rue d'Ulm 75248 Paris Cedex 05, France.

 

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.

 

Journal: Cell Reports

 

Link: http://www.cell.com/cell-reports/abstract/S2211-1247(15)00947-X