title: Mammary epithelial cell phenotype disruption in vitro and in vivo through ERalpha36 overexpression.
abstract: Estrogen receptor alpha 36 (ERα36) is a variant of the canonical estrogen receptor alpha (ERα66), widely expressed in hormone sensitive cancer cells and whose high expression level correlates with a poor survival prognosis for breast cancer patients. While ERα36 activity have been related to breast cancer progression or acquired resistance to treatment, expression level and location of ERα36 are poorly documented in the normal mammary gland. Therefore, we explored the consequences of a ERα36 overexpression in vitro in MCF-10A normal mammary epithelial cells and in vivo in a unique model of MMTV-ERα36 transgenic mouse strain wherein ERα36 mRNA was specifically expressed in the mammary gland. By a combination of bioinformatics and computational analyses of microarray data, we identified hierarchical gene networks, downstream of ERα36 and modulated by the JAK2/STAT3 signaling pathway. Concomitantly, ERα36 overexpression lowered proliferation rate but enhanced migration potential and resistance to staurosporin-induced apoptosis of the MCF-10A cell line. In vivo, ERα36 expression led to duct epithelium thinning and disruption in adult but not in prepubescent mouse mammary gland. These phenotypes correlated with a loss of E-cadherin expression. Here, we show that an enhanced expression of ERα36 is sufficient, by itself, to disrupt normal breast epithelial phenotype in vivo and in vitro through a dominant-positive effect on nongenomic estrogen signaling pathways. These results also suggest that, in the presence of adult endogenous steroid levels, ERα36 overexpression in vivo contributes to alter mammary gland architecture which may support pre-neoplastic lesion and augment breast cancer risk.
authors.affiliation: CNRS-Université de Lorraine, UMR 7039, Centre de Recherche en Automatique de Nancy, BP70239, Vandœuvre-lès-Nancy, France.
authors.forename: Charlène
authors.initials: C
authors.lastname: Thiebaut
authors.affiliation: CNRS-Université de Lorraine, UMR 7039, Centre de Recherche en Automatique de Nancy, BP70239, Vandœuvre-lès-Nancy, France.
authors.forename: Clémence
authors.initials: C
authors.lastname: Chamard-Jovenin
authors.affiliation: CNRS-Université de Lorraine, UMR 7039, Centre de Recherche en Automatique de Nancy, BP70239, Vandœuvre-lès-Nancy, France.
authors.forename: Amand
authors.initials: A
authors.lastname: Chesnel
authors.affiliation: CNRS-Université de Lorraine, UMR 7039, Centre de Recherche en Automatique de Nancy, BP70239, Vandœuvre-lès-Nancy, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Morel
authors.affiliation: CNRS-Université de Lorraine, UMR 7039, Centre de Recherche en Automatique de Nancy, BP70239, Vandœuvre-lès-Nancy, France.
authors.forename: El-Hadi
authors.initials: EH
authors.lastname: Djermoune
authors.affiliation: CNRS-Université de Lorraine, UMR 7039, Centre de Recherche en Automatique de Nancy, BP70239, Vandœuvre-lès-Nancy, France.
authors.forename: Taha
authors.initials: T
authors.lastname: Boukhobza
authors.affiliation: CNRS-Université de Lorraine, UMR 7039, Centre de Recherche en Automatique de Nancy, BP70239, Vandœuvre-lès-Nancy, France.
authors.forename: Hélène
authors.identifier: http://orcid.org/0000-0002-9697-3901
authors.initials: H
authors.lastname: Dumond
mesh_terms: D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D045744:Cell Line, Tumor; D002465:Cell Movement; D004847:Epithelial Cells / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics*; D006801:Humans; D042361:Mammary Glands, Human / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D047628:Estrogen Receptor alpha