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Communication Dans Un Congrès Année : 2017

ERα36 expression: a key breast cancer risk factor?

Résumé

Estrogen receptor alpha 36 (ERα36) is a variant of the canonical estrogen receptor alpha (ERα66), whose high expression level correlates with a poor survival prognosis for breast cancer patients. While our previous results indicated that a high ERα36 expression level correlates with hormone independent growth and enhanced metastatic potential (Chamard-Jovenin et al, 2015; doi: 10.1186/s12918-015-0178-7) the mechanisms of ERα36 expression onset and the consequences for the normal mammary gland are poorly documented. Therefore, we explored (i) the methylation status of ERα36 promoter in 60 mammary tumor samples and (ii) 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 the human ERα36 mRNA was specifically expressed in the mammary gland. Our data indicate a marked correlation between promoter methylation and ERα36 expression. Concomitantly, ERα36 overexpression lowered proliferation rate but enhanced migration and survival of the MCF-10A cell line. By a combination of bioinformatics and computational analyses of microarray data, we identified hierarchical gene networks, downstream of ERα36. In vivo, human ERα36 expression led to duct epithelium thinning and E-cadherin expression loss in adult but not prepubescent mice. Here, we show that ERα36 expression could be driven, at least in part, by epigenetic mechanisms. Moreover, 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 endogenous estradiol, ERα36 overexpression in vivo contributes to alter mammary gland architecture which may support pre-neoplastic lesion and augment breast cancer risk.

Domaines

Cancer
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Dates et versions

hal-01665545 , version 1 (16-12-2017)

Identifiants

  • HAL Id : hal-01665545 , version 1

Citer

Charlène Thiébaut, Clémence Chamard-Jovenin, Amand Chesnel, Chloé Morel, Isabelle Grillier-Vuissoz, et al.. ERα36 expression: a key breast cancer risk factor?. 2nd EACR-OECI Conference Making it Personal - Cancer Precision Medicine, Mar 2017, Amsterdam, Netherlands. ⟨hal-01665545⟩
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