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Membrane expression of the estrogen receptor ER? is required for intercellular communications in the mammary epithelium.

ABSTRACT: 17?-Estradiol induces the postnatal development of mammary gland and influences breast carcinogenesis by binding to the estrogen receptor ER?. ER? acts as a transcription factor but also elicits rapid signaling through a fraction of ER? expressed at the membrane. Here, we have used the C451A-ER? mouse model mutated for the palmitoylation site to understand how ER? membrane signaling affects mammary gland development. Although the overall structure of physiological mammary gland development is slightly affected, both epithelial fragments and basal cells isolated from C451A-ER? mammary glands failed to grow when engrafted into cleared wild-type fat pads, even in pregnant hosts. Similarly, basal cells purified from hormone-stimulated ovariectomized C451A-ER? mice did not produce normal outgrowths. Ex vivo, C451A-ER? basal cells displayed reduced matrix degradation capacities, suggesting altered migration properties. More importantly, C451A-ER? basal cells recovered in vivo repopulating ability when co-transplanted with wild-type luminal cells and specifically with ER?-positive luminal cells. Transcriptional profiling identified crucial paracrine luminal-to-basal signals. Altogether, our findings uncover an important role for membrane ER? expression in promoting intercellular communications that are essential for mammary gland development.

SUBMITTER: Gagniac L

PROVIDER: S-EPMC7075076 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Membrane expression of the estrogen receptor ERα is required for intercellular communications in the mammary epithelium.

Gagniac Laurine L Rusidzé Mariam M Boudou Frederic F Cagnet Stephanie S Adlanmerini Marine M Jeannot Pauline P Gaide Nicolas N Giton Frank F Besson Arnaud A Weyl Ariane A Gourdy Pierre P Raymond-Letron Isabelle I Arnal Jean-Francois JF Brisken Cathrin C Lenfant Francoise F

Development (Cambridge, England) 20200311 5

17β-Estradiol induces the postnatal development of mammary gland and influences breast carcinogenesis by binding to the estrogen receptor ERα. ERα acts as a transcription factor but also elicits rapid signaling through a fraction of ERα expressed at the membrane. Here, we have used the C451A-ERα mouse model mutated for the palmitoylation site to understand how ERα membrane signaling affects mammary gland development. Although the overall structure of physiological mammary gland development is sl ...[more]

PMID: 32098763

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Project description: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.

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Membrane expression of the estrogen receptor ER? is required for intercellular communications in the mammary epithelium.

Publications

Membrane expression of the estrogen receptor ERα is required for intercellular communications in the mammary epithelium.

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