Abstract
IntroductionAlthough 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.MethodsWe 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.ResultsWe 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.ConclusionsThis 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.
Highlights
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
It is believed that elucidating the cellular hierarchy of differentiation in the normal breast epithelium and understanding the mechanisms by which ovarian steroid hormones control the proliferation of mammary stem/progenitor cells would give insights into the origin of different subtypes of breast cancer
Normal mammary epithelial cells with high aldehyde dehydrogenase (ALDH) enzymatic activity are positive for ALDH1A1 or ALDH1A3 by immunostaining To identify in situ the ALDH+ human mammary epithelial cell population previously shown to be associated with stem/progenitor properties in functional assays, we sought to identify the ALDH isoforms associated with this enzymatic activity
Summary
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. The mammary gland tissue undergoes morphogenesis postnatally, a process most likely sustained by mammary stem and progenitor cells and controlled by systemic factors such as the ovarian steroid hormones estrogen and progesterone. It is believed that elucidating the cellular hierarchy of differentiation in the normal breast epithelium and understanding the mechanisms by which ovarian steroid hormones control the proliferation of mammary stem/progenitor cells would give insights into the origin of different subtypes of breast cancer
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