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Breast Cancer Research
Published in: Breast Cancer Research 3/2014

Open Access 01-06-2014 | Research article

Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium

Authors: Gabriella Honeth, Sara Lombardi, Christophe Ginestier, Minhee Hur, Rebecca Marlow, Bharath Buchupalli, Ireneusz Shinomiya, Patrycja Gazinska, Silvia Bombelli, Vernie Ramalingam, Anand D Purushotham, Sarah E Pinder, Gabriela Dontu

Published in: Breast Cancer Research | Issue 3/2014

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Abstract

Introduction

Although estrogen and progesterone play a key role in normal mammary development and in breast cancer, the potential for proliferation and lineage differentiation as well as origin of cells that express the estrogen receptor (ER) in normal breast epithelium are not known. Some evidence suggests that normal human mammary stem/progenitor cells are ER–, but the identity of these cells and the cellular hierarchy of breast epithelium are still subjects of controversy. It is likely that elucidation of these aspects will bring insight into the cellular origin of breast cancer subtypes.

Methods

We used fluorescence-activated cell sorting of primary human mammary epithelial cells along with in vitro and in vivo functional assays to examine the hierarchic relation between cells with aldehyde dehydrogenase enzymatic activity (ALDH+ cells) and ER+ cells in the normal human breast epithelium. We assessed the proliferation and lineage differentiation potential of these cells in vitro and in vivo. A gene reporter assay was used to separate live ER+ and ER– mammary epithelial cells. With shRNA-mediated knockdown, we investigated the role of ALDH isoforms in the functionality of mammary epithelial progenitor cells.

Results

We describe a cellular hierarchy in the normal human mammary gland in which ER–/ALDH+ cells with functional properties of stem/progenitor cells generate ER+ progenitor cells, which in turn give rise to cells of luminal lineage. We show that the ALDH1A1 isoform, through its function in the retinoic acid metabolism, affects the proliferation and/or early differentiation of stem/progenitor cells and is important for branching morphogenesis.

Conclusions

This study presents direct evidence that ER+ cells are generated by ER–/ALDH+ stem/progenitor cells. We also show that ER+ cells are able to generate cell progeny of luminal lineage in vitro and in vivo. Loss of ALDH1A1 function impairs this process, as well as branching morphogenesis and clonogenicity in suspension culture. This latter effect is reversed by treatment with retinoic acid.
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Metadata
Title
Aldehyde dehydrogenase and estrogen receptor define a hierarchy of cellular differentiation in the normal human mammary epithelium
Authors
Gabriella Honeth
Sara Lombardi
Christophe Ginestier
Minhee Hur
Rebecca Marlow
Bharath Buchupalli
Ireneusz Shinomiya
Patrycja Gazinska
Silvia Bombelli
Vernie Ramalingam
Anand D Purushotham
Sarah E Pinder
Gabriela Dontu
Publication date
01-06-2014
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2014
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr3663

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