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.
Highlights
Twenty years ago, steroid hormones, especially sex hormones, were shown to stimulate gene transcription through binding a transcription factor in the cell nucleus called a nuclear steroid receptor
Since ERα36 has been shown to collaborate with other estrogen or growth factor receptors in numerous cancer cells, our results raise the possibility that an excess of ERα36 protein could be a dominant positive activator of either the G protein-coupled estrogen receptor GPER, or the EGFR downstream signaling
JAK2/STAT3 signaling was reported to be involved in GPER signaling in the hypothalamus and SKBR-3 breast cancer cells [45, 46]
Summary
Steroid hormones, especially sex hormones, were shown to stimulate gene transcription through binding a transcription factor in the cell nucleus called a nuclear steroid receptor. The so-called “genomic estrogen signaling” is mediated by direct actions of nuclearlocalized estrogen receptors (ERs: ERalpha and ERbeta) as ligand-induced transcription. ERα36-dependent disruption of mammary epithelium (fund 2016; recipient HD) and the Region Lorraine for a half PhD fellowship http://www.lorraine.eu (CC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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