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Steroid hormones modulate H19 gene expression in both mammary gland and uterus

Oncogene volume 18, pages 4460–4473 (1999)Cite this article

Abstract

H19 is an imprinted and developmentally regulated gene whose product remains apparently untranslated. In a previous study on breast adenocarcinomas, we reported that overexpression of the H19 gene was significantly correlated with the presence of steroid receptors, suggesting the putative role of hormones in H19 transcription. To determine the mode of steroid action, we have detected levels of H19 RNA synthesis during mammary gland development by in situ hybridization (ISH): two peaks of H19 transcription occur during puberty and pregnancy. Furthermore, we demonstrated by ISH that in the uterus H19 RNA synthesis is high during estrus and metestrus phases. To test steroid control of H19 transcription, ovariectomized and adrenalectomized mice were supplemented, 1 week after surgery, with 17-β-estradiol (E2, 20 μg/kg/day), progesterone (P, 1 mg/kg/day) or corticosterone (B, 0.3 mg/kg/day) for 2 weeks. According to ISH data, E2 and to a lesser extent B stimulated H19 transcription in the uterus, whereas P inhibited it. To confirm the in vivo results, in vitro experiments were performed using cultures of MCF-7 cells (a hormone-sensitive mammary cell line). E2 stimulated the endogenous H19 gene of this cell line and tamoxifen inhibited this effect. Furthermore, we performed transient cotransfections in MCF-7, in HBL-100 (another hormone-sensitive mammary cell line) and in BT-20 (a hormone-insensitive mammary cell line) with various constructs of ERα (WT or mutated) and PR-A, in presence or absence of steroid hormones. We demonstrated that ERα up-regulated the H19 promoter in MCF-7 and in HBL-100, whereas PR-A did not have any effect per se. Moreover, in MCF-7, PR-A antagonized clearly the ERα-mediated promoter enhancement, but in HBL-100 this counteracting effect on the ERα up-regulation was not found. Interestingly, the same experiments performed in BT-20 cell line provided very similar results as those obtained in MCF-7 cells, with a clear down-regulation mediated by PR-A on the H19 promoter. All these in vitro data are in agreement with in vivo results. In addition, data obtained with ERα mutants indicate that H19 promoter activation is both ligand-dependent and ligand-independent. We have thus demonstrated that H19 gene expression is controlled by steroid hormones; furthermore, this gene is highly expressed in hormone-sensitive organs when the hormonal stimulation is accompanied with a morphological repair.

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Acknowledgements

We would like to thank Dr Anne Chauchereau (INSERM U135, University Paris-Sud, Le Kremlin-Bicêtre), Dr Gwendal Lazennec (Montpellier) and Dr Franck Delaunay for graciously providing wild-type progesterone, wild-type and E domain mutated estrogen receptors, AF-1 mutated ones, respectively. We thank also Dr Brigitte Fournier (Novartis, Bale) for her generous gift of the ERE-Luc vector. Thanks to Dr Julie Kerr-Conte (Lille) and Dr Victor Nurcombe (University of Queensland, St. Lucia, Brisbane, Australia) for critical reading of the manuscript. We are indebted to Dr Bernard Vandenbunder (Institut de Biologie Moléculaire, Lille) for our training in his laboratory and to Fatima Bouali for her help in in situ hybridization technique. We are grateful to Chantal Pennel (Centre anti-cancéreux Oscar Lambret, Lille) and Isabelle Pollet for their help in histological methods. This work was supported by grants from Pasteur Institute of Lille. Jean-Jacques Curgy holds grants from the Fédération des Groupements des Entreprises Françaises dans la Lutte contre le Cancer (FéGEFLUC), from the Comité Nord de la Ligue Nationale contre le Cancer and from the NORGINE PHARMA laboratories (Paris). Eric Adriaenssens is a recipient of an ARC (Association pour la Recherche sur le Cancer) fellowship.

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  1. E Adriaenssens

    Present address: Immunopathologie Cellulaire des Maladies Infectieuses, UMR 8527, BP 447, Lille cedex, 59021, France

Authors and Affiliations

  1. Laboratoire de Biologie du Développement, UPRES EA 1033, SN3, U.S.T. de Lille, Villeneuve d'Ascq cedex, 59655, France

    E Adriaenssens, S Lottin, T Dugimont, W Fauquette, B Boilly & J J Curgy

  2. Faculté des Sciences Jean Perrin, Université d'Artois, Lens cedex, 62307, France

    T Dugimont

  3. Immunopathologie Cellulaire des Maladies Infectieuses, URA 1854, Lille cedex, BP 447, 59021, France

    J Coll

  4. Centre de Biologie Cellulaire, Laboratoire de Neuroendocrinologie du Développement, U.S.T. de Lille, Villeneuve d'Ascq cedex, 59655, France

    J P Dupouy

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Adriaenssens, E., Lottin, S., Dugimont, T. et al. Steroid hormones modulate H19 gene expression in both mammary gland and uterus. Oncogene 18, 4460–4473 (1999). https://doi.org/10.1038/sj.onc.1202819

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