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Open Access Highly Accessed Research article

Phenotypic and functional characterisation of the luminal cell hierarchy of the mammary gland

Mona Shehata1*, Andrew Teschendorff2, Gemma Sharp1, Nikola Novcic1, I Alasdair Russell1, Stefanie Avril13, Michael Prater1, Peter Eirew4, Carlos Caldas5678, Christine J Watson9 and John Stingl1*

Author Affiliations

1 Mammary Stem Cell Laboratory, Cancer Research UK, Cambridge Research Institute, Li Ka-Shing Centre, Robinson Way, Cambridge CB2 0RE, UK

2 Statistical Cancer Genomics, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK

3 Present address: Department of Pathology, Technical University Munich, 21 Arcis Street, Munich 80333, Germany

4 Department of Molecular Oncology, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver V5Z 1L3, Canada

5 Department of Oncology, University of Cambridge, Worts Causeway, Cambridge CB1 9RN, UK

6 Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge University Hospital NHS, Foundation Trust and NIHR Cambridge Biomedical Research Centre, Box 97 Hills Road, Cambridge CB2 2QQ, UK

7 Cambridge Experimental Cancer Medicine Centre, Cancer Research UK, Cambridge Research Institute, Li Ka-Shing Centre, Robinson Way, Cambridge CB2 0RE, UK

8 Breast Cancer Functional Genomics Laboratory, Cancer Research UK, Cambridge Research Institute, Li Ka-Shing Centre, Robinson Way, Cambridge CB2 0RE, UK

9 Department of Pathology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK

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Breast Cancer Research 2012, 14:R134  doi:10.1186/bcr3334

Published: 22 October 2012

Abstract

Introduction

The organisation of the mammary epithelial hierarchy is poorly understood. Our hypothesis is that the luminal cell compartment is more complex than initially described, and that an understanding of the developmental relationships within this lineage will help in understanding the cellular context in which breast tumours occur.

Methods

We used fluorescence-activated cell sorting along with in vitro and in vivo functional assays to examine the growth and differentiation properties of distinct subsets of human and mouse mammary epithelial cells. We also examined how loss of steroid hormones influenced these populations in vivo. Gene expression profiles were also obtained for all the purified cell populations and correlated to those obtained from breast tumours.

Results

The luminal cell compartment of the mouse mammary gland can be resolved into nonclonogenic oestrogen receptor-positive (ER+) luminal cells, ER+ luminal progenitors and oestrogen receptor-negative (ER-) luminal progenitors. The ER+ luminal progenitors are unique in regard to cell survival, as they are relatively insensitive to loss of oestrogen and progesterone when compared with the other types of mammary epithelial cells. Analysis of normal human breast tissue reveals a similar hierarchical organisation composed of nonclonogenic luminal cells, and relatively differentiated (EpCAM+CD49f+ALDH-) and undifferentiated (EpCAM+CD49f+ALDH+) luminal progenitors. In addition, approximately one-quarter of human breast samples examined contained an additional population that had a distinct luminal progenitor phenotype, characterised by low expression of ERBB3 and low proliferative potential. Parent-progeny relationship experiments demonstrated that all luminal progenitor populations in both species are highly plastic and, at low frequencies, can generate progeny representing all mammary cell types. The ER- luminal progenitors in the mouse and the ALDH+ luminal progenitors in the human appear to be analogous populations since they both have gene signatures that are associated with alveolar differentiation and resemble those obtained from basal-like breast tumours.

Conclusion

The luminal cell compartment in the mammary epithelium is more heterogeneous than initially perceived since progenitors of varying levels of luminal cell differentiation and proliferative capacities can be identified. An understanding of these cells will be essential for understanding the origins and the cellular context of human breast tumours.