%0 Journal Article
%T Identification of Estrogen Receptor Dimer Selective Ligands Reveals Growth-Inhibitory Effects on Cells That Co-Express ER¦Á and ER¦Â
%A Emily Powell
%A Erin Shanle
%A Ashley Brinkman
%A Jun Li
%A Sunduz Keles
%A Kari B. Wisinski
%A Wei Huang
%A Wei Xu
%J PLOS ONE
%D 2012
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0030993
%X Estrogens play essential roles in the progression of mammary and prostatic diseases. The transcriptional effects of estrogens are transduced by two estrogen receptors, ER¦Á and ER¦Â, which elicit opposing roles in regulating proliferation: ER¦Á is proliferative while ER¦Â is anti-proliferative. Exogenous expression of ER¦Â in ER¦Á-positive cancer cell lines inhibits cell proliferation in response to estrogen and reduces xenografted tumor growth in vivo, suggesting that ER¦Â might oppose ER¦Á's proliferative effects via formation of ER¦Á/¦Â heterodimers. Despite biochemical and cellular evidence of ER¦Á/¦Â heterodimer formation in cells co-expressing both receptors, the biological roles of the ER¦Á/¦Â heterodimer remain to be elucidated. Here we report the identification of two phytoestrogens that selectively activate ER¦Á/¦Â heterodimers at specific concentrations using a cell-based, two-step high throughput small molecule screen for ER transcriptional activity and ER dimer selectivity. Using ER¦Á/¦Â heterodimer-selective ligands at defined concentrations, we demonstrate that ER¦Á/¦Â heterodimers are growth inhibitory in breast and prostate cells which co-express the two ER isoforms. Furthermore, using Automated Quantitative Analysis (AQUA) to examine nuclear expression of ER¦Á and ER¦Â in human breast tissue microarrays, we demonstrate that ER¦Á and ER¦Â are co-expressed in the same cells in breast tumors. The co-expression of ER¦Á and ER¦Â in the same cells supports the possibility of ER¦Á/¦Â heterodimer formation at physio- and pathological conditions, further suggesting that targeting ER¦Á/¦Â heterodimers might be a novel therapeutic approach to the treatment of cancers which co-express ER¦Á and ER¦Â.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0030993