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 preneoplastic lesion and augment breast cancer risk
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Submitted on : Monday, March 20, 2017 - 10:40:48 AM
Last modification on : Thursday, September 12, 2019 - 10:51:45 AM

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Charlène Thiébaut, Clémence Chamard-Jovenin, Amand Chesnel, Chloé Morel, El-Hadi Djermoune, et al.. Mammary epithelial cell phenotype disruption in vitro and in vivo through ERalpha36 overexpression. PLoS ONE, Public Library of Science, 2017, 12 (3), pp.e0173931. ⟨10.1371/journal.pone.0173931⟩. ⟨hal-01492524⟩

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