Estrogen receptor beta1 and the beta2/betacx isoforms in nonneoplastic endometrium and in endometrioid carcinoma

Estrogen receptor beta (ERbeta) has five carboxyl-terminal (C-terminal) isoforms derived from alternative splicing. ERbeta1 is the wild-type receptor whereas ERbeta2/betacx lacks the activation function (AF)-2 core essential for ligand-dependent transcriptional activation and so behaves as a dominant-negative receptor affecting the function of ERalpha. The objective of this study was to analyze the expression of ERbeta1 and ERbeta2/betacx isoforms in nonneoplastic endometrium and endometrioid carcinoma. The study was conducted on samples of 22 proliferative endometrium, 15 secretory endometrium, 20 simple hyperplasia (without atypia), and 26 endometrioid carcinomas. The transcript and protein levels were determined by semiquantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry, respectively. For the detection of ERbeta2/betacx protein, a polyclonal antibody was raised to its unique C-terminus, characterized, and used in immunohistochemistry. The two ERbeta isoforms are expressed in the proliferative and secretory phase endometrium with no significant change in their relative levels. The levels of the ERbeta1 isoform were lower as compared to the levels of ERbeta2 in all the groups studied. Expression of ERbeta2/betacx was decreased in endometrioid carcinoma as compared to proliferative endometrium (P < 0.01). A significant decrease of the ERbeta2/ERbetacx transcript was observed with higher grade tumors (P = 0.041). Progesterone receptor (PR) expression was not influenced by either of the ERbeta isoforms which was observed by logistic regression analysis in all the groups. The coexpression of ERbeta2/betacx with ERalpha did not affect PR levels (logistic regression analysis). Thus, we conclude in the human endometrium, there is significant ERbeta2/betacx isoform expression and alterations in its levels could be involved in endometrial cancer progression.