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Open Access Highly Accessed Research article

Oestrogen increases the activity of oestrogen receptor negative breast cancer stem cells through paracrine EGFR and Notch signalling

Hannah Harrison1, Bruno M Simões2, Lynsey Rogerson1, Sacha J Howell3, Göran Landberg14 and Robert B Clarke2*

Author Affiliations

1 Molecular Pathology Group, Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, Paterson Institute for Cancer Research, Manchester, M20 4BX, UK

2 Breast Biology Group, Institute of Cancer Sciences, University of Manchester, Paterson Institute for Cancer Research, Manchester, M20 4BX, UK

3 Department of Medical Oncology, The University of Manchester, The Christie NHS Foundation Trust, Manchester, M20 4BX, UK

4 Sahlgrenska Cancer Center, Institute of Biomedicine, 405 30 Göteborg, Sweden

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Breast Cancer Research 2013, 15:R21  doi:10.1186/bcr3396

Published: 8 March 2013

Abstract

Introduction

Although oestrogen is essential for the development of the normal breast, adult mammary stem cells are known to be oestrogen receptor alpha (ER) negative and rely on paracrine signals in the mammary epithelium for mediation of developmental cues. However, little is known about how systemic oestrogen regulates breast cancer stem cell (CSC) activity.

Methods

Here, we tested the effects of oestrogen on CSC activity in vitro and in vivo and investigated which paracrine signalling pathways locally mediate oestrogen effects.

Results

CSC-enriched populations (ESA+CD44+CD24low) sorted from ER positive patient derived and established cell lines have low or absent ER expression. However, oestrogen stimulated CSC activity demonstrated by increased mammosphere and holoclone formation in vitro and tumour formation in vivo. This effect was abrogated by the anti-oestrogen tamoxifen or ER siRNA. These data suggest that the oestrogen response is mediated through paracrine signalling from non-CSCs to CSCs. We have, therefore, investigated both epidermal growth factor (EGF) and Notch receptor signals downstream of oestrogen. We demonstrate that gefitinib (epidermal growth factor receptor (EGFR) inhibitor) and gamma secretase inhibitors (Notch inhibitor) block oestrogen-induced CSC activity in vitro and in vivo but GSIs more efficiently reduce CSC frequency.

Conclusions

These data establish that EGF and Notch receptor signalling pathways operate downstream of oestrogen in the regulation of ER negative CSCs.