Mammary epithelial cell phenotype disruption in vitro and in vivo through ERalpha36 overexpression

International audienceEstrogen receptor alpha 36 (ERα36) is a variant of the canonical estrogen receptor alpha(ERα66), widely expressed in hormone sensitive cancer cells and whose high expressionlevel correlates with a poor survival prognosis for breast cancer patients. While ERα36 activityhave been related to breast cancer progression or acquired resistance to treatment,expression level and location of ERα36 are poorly documented in the normal mammarygland. Therefore, we explored the consequences of a ERα36 overexpression in vitro inMCF-10A normal mammary epithelial cells and in vivo in a unique model of MMTV-ERα36transgenic mouse strain wherein ERα36 mRNA was specifically expressed in the mammarygland. By a combination of bioinformatics and computational analyses of microarray data,we identified hierarchical gene networks, downstream of ERα36 and modulated by theJAK2/STAT3 signaling pathway. Concomitantly, ERα36 overexpression lowered proliferationrate but enhanced migration potential and resistance to staurosporin-induced apoptosisof the MCF-10A cell line. In vivo, ERα36 expression led to duct epithelium thinning and disruptionin adult but not in prepubescent mouse mammary gland. These phenotypes correlatedwith a loss of E-cadherin expression. Here, we show that an enhanced expression ofERα36 is sufficient, by itself, to disrupt normal breast epithelial phenotype in vivo and in vitrothrough a dominant-positive effect on nongenomic estrogen signaling pathways. Theseresults also suggest that, in the presence of adult endogenous steroid levels, ERα36 overexpressionin vivo contributes to alter mammary gland architecture which may support preneoplasticlesion and augment breast cancer ris