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Estrogen receptor coregulators and pioneer factors: the orchestrators of mammary gland cell fate and development.

ABSTRACT: The steroid hormone, 17?-estradiol (E2), plays critical role in various cellular processes such as cell proliferation, differentiation, migration and apoptosis, and is essential for reproduction and mammary gland development. E2 actions are mediated by two classical nuclear hormone receptors, estrogen receptor ? and ? (ERs). The activity of ERs depends on the coordinated activity of ligand binding, post-translational modifications (PTMs), and importantly the interaction with their partner proteins called "coregulators." Because coregulators are proved to be crucial for ER transcriptional activity, and majority of breast cancers are ER? positive, an increased interest in the field has led to the identification of a large number of coregulators. In the last decade, gene knockout studies using mouse models provided impetus to our further understanding of the role of these coregulators in mammary gland development. Several coregulators appear to be critical for terminal end bud (TEB) formation, ductal branching and alveologenesis during mammary gland development. The emerging studies support that, coregulators along with the other ER partner proteins called "pioneer factors" together contribute significantly to E2 signaling and mammary cell fate. This review discusses emerging themes in coregulator and pioneer factor mediated action on ER functions, in particular their role in mammary gland cell fate and development.

SUBMITTER: Manavathi B

PROVIDER: S-EPMC4207046 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Estrogen receptor coregulators and pioneer factors: the orchestrators of mammary gland cell fate and development.

Manavathi Bramanandam B Samanthapudi Venkata S K VS Gajulapalli Vijay Narasimha Reddy VN

Frontiers in cell and developmental biology 20140812

The steroid hormone, 17β-estradiol (E2), plays critical role in various cellular processes such as cell proliferation, differentiation, migration and apoptosis, and is essential for reproduction and mammary gland development. E2 actions are mediated by two classical nuclear hormone receptors, estrogen receptor α and β (ERs). The activity of ERs depends on the coordinated activity of ligand binding, post-translational modifications (PTMs), and importantly the interaction with their partner protei ...[more]

PMID: 25364741

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Project description:Background and aimsDuring liver development, bipotent progenitor cells differentiate into hepatocytes and biliary epithelial cells to ensure a functional liver required to maintain organismal homeostasis. The developmental cues controlling the differentiation of committed progenitors into these cell types, however, are incompletely understood. Here, we discover an essential role for estrogenic regulation in vertebrate liver development to affect hepatobiliary fate decisions.Approach and resultsExposure of zebrafish embryos to 17β-estradiol (E2) during liver development significantly decreased hepatocyte-specific gene expression, liver size, and hepatocyte number. In contrast, pharmacological blockade of estrogen synthesis or nuclear estrogen receptor (ESR) signaling enhanced liver size and hepatocyte marker expression. Transgenic reporter fish demonstrated nuclear ESR activity in the developing liver. Chemical inhibition and morpholino knockdown of nuclear estrogen receptor 2b (esr2b) increased hepatocyte gene expression and blocked the effects of E2 exposure. esr2b-/- mutant zebrafish exhibited significantly increased expression of hepatocyte markers with no impact on liver progenitors, other endodermal lineages, or vasculature. Significantly, E2-stimulated Esr2b activity promoted biliary epithelial differentiation at the expense of hepatocyte fate, whereas loss of esr2b impaired biliary lineage commitment. Chemical and genetic epistasis studies identified bone morphogenetic protein (BMP) signaling as a mediator of the estrogen effects. The divergent impact of estrogen on hepatobiliary fate was confirmed in a human hepatoblast cell line, indicating the relevance of this pathway for human liver development.ConclusionsOur studies identify E2, esr2b, and downstream BMP activity as important regulators of hepatobiliary fate decisions during vertebrate liver development. These results have significant clinical implications for liver development in infants exposed to abnormal estrogen levels or estrogenic compounds during pregnancy.

Project description:BackgroundCross-talk between the aryl hydrocarbon receptor (AHR) and the estrogen receptor (ER) plays a major role in signaling processes in female reproductive organs.ObjectivesWe investigated the influence of the AHR ligand 3-methylcholanthrene (3-MC) on ER-mediated signaling in mammary gland tissue of ovariectomized (ovx) rats.MethodsAfter 14 days of hormonal decline, ovx rats were treated for 3 days with 4 μg/kg 17β-estradiol (E2), 15 mg/kg 8-prenylnaringenin (8-PN), 15 mg/kg 3-MC, or a combination of these compounds (E2 + 3-MC, 8-PN + 3-MC). Whole-mount preparations of the mammary gland were used to count terminal end buds (TEBs). Protein expression studies (immunohistochemistry, immunofluorescence), a cDNA microarray, pathway analyses, and quantitative real-time polymerase chain reaction (qPCR) were performed to evaluate the interaction between AHR- and ER-mediated signaling pathways.ResultsE2 treatment increased the number of TEBs and the levels of Ki-67 protein and progesterone receptor (PR); this treatment also changed the expression of 325 genes by more than 1.5-fold. Although 3-MC treatment alone had marginal impact on gene or protein expression, when rats were co-treated with 3-MC and E2, 3-MC strongly inhibited E2-induced TEB development, protein synthesis, and the expression of nearly half of E2-induced genes. This inhibitory effect of 3-MC was partially mirrored when 8-PN was used as an ER ligand. The anti-estrogenicity of ligand-activated AHR was at least partly due to decreased protein levels of ERα in ductal epithelial cells.ConclusionOur data show transcriptome-wide anti-estrogenic properties of ligand-activated AHR on ER-mediated processes in the mammary gland, thereby contributing an explanation for the chemopreventive and endocrine-disrupting potential of AHR ligands.CitationHelle J, Bader MI, Keiler AM, Zierau O, Vollmer G, Chittur SV, Tenniswood M, Kretzschmar G. 2016. Cross-talk in the female rat mammary gland: influence of aryl hydrocarbon receptor on estrogen receptor signaling. Environ Health Perspect 124:601-610; http://dx.doi.org/10.1289/ehp.1509680.

Dataset Information

Estrogen receptor coregulators and pioneer factors: the orchestrators of mammary gland cell fate and development.

Publications

Estrogen receptor coregulators and pioneer factors: the orchestrators of mammary gland cell fate and development.

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