The estrogen receptor (ER)alpha46, the “forgotten” isoform which emerges as the third estrogen receptor. – EmERgence46

Although estrogens, produced by ovaries, are key protective molecules in vascular, bone physiology and glucose metabolism, their proliferative actions on breast and uterus epithelium limit their long-term use at menopause. Estrogen receptor (ER) a but not ERß, mediates these effects and beside the well-characterized ERa66 isoform, a shorter one of 46kDa (ERa46) was shown to elicit different properties in vitro. The full length isoform of 66kD (ERa66) has, to date, retained most of the attention, although smaller forms are observed on Western blot. Indeed, these bands are most of the time neglected as they are interpreted as degradation products. However, overexpression of ERa46 in vitro inhibits the proliferative response to estrogen mediated by ERa66 in the MCF7 breast cancer cell line.
As a consequence of a lack of appropriate tools and models, very little information is available about the expression and the role of ERa46 in physiology (in vivo). Team1 has shown that mice deficient in ERa66 and expressing only the short form ERa49 (for reasons of construction, functionally similar to the ERa46) is sufficient to convey the benefits of 17ß-estradiol (E2) but not its proliferative effects on the endometrium. Finally, many unpublished results by Team1 provide evidence of the existence and abundance of ERa46 both in mice tissues and in breast cancer tumors.
The aim of the project, involving physiologists, chemists and physicists, is to develop new original experimental approaches to detect and highlight the role of ERa46 in vivo. We propose here a pioneering methodology to quantify the expression pattern and regulation of ERa46 and an original mouse model selectively deficient for this isoform. Team2 will develop a method to detect ERa46 based on its molecular signature recorded using Raman spectroscopy and original nanoparticle-based supports enhancing the Raman signal. This new technology will be compared to western assays in order to discriminate ERa66 form ERa46 in mice tissue under different oestrogenic condition as well as in human breast cancer tumors. Team1 plan to define the role of ERa46 through the phenotyping of a new mouse model selectively deficient for ERa46 regarding its role in fertility, uterine proliferation and vasculoprotective actions of E2.
The complementary expertise of the two teams would allow to propose, beside ERa66 and ERß, ERa46 as the third Estrogen Receptor. The purpose of the present project is also to provide new insights into the mechanism by which estrogens exert their beneficial (vasculoprotectrive) and deleterious (proliferative) effects in order to confirm the interest and the feasibility of an innovative strategy based on the selective/ preferential activation of the "forgotten” estrogen receptor isoform, ERa46. Finally, this project could propose a new technique to perform systematic research studies and potentially to develop a new diagnostic kit in monitoring breast cancer.