Estrogen receptor β1 and the β2/βcx isoforms in nonneoplastic endometrium and in endometrioid carcinoma

Estrogen receptor beta (ERβ) has five carboxyl-terminal (C-terminal) isoforms derived from alternative splicing. ERβ1 is the wild-type receptor whereas ERβ2/βcx 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 ERα. The objective of this study was to analyze the expression of ERβ1 and ERβ2/βcx 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 ERβ2/βcx protein, a polyclonal antibody was raised to its unique C-terminus, characterized, and used in immunohistochemistry. The two ERβ isoforms are expressed in the proliferative and secretory phase endometrium with no significant change in their relative levels. The levels of the ERβ1 isoform were lower as compared to the levels of ERβ2 in all the groups studied. Expression of ERβ2/βcx was decreased in endometrioid carcinoma as compared to proliferative endometrium (P < 0.01). A significant decrease of the ERβ2/ERβcx transcript was observed with higher grade tumors (P = 0.041). Progesterone receptor (PR) expression was not influenced by either of the ERβ isoforms which was observed by logistic regression analysis in all the groups. The coexpression of ERβ2/βcx with ERα did not affect PR levels (logistic regression analysis). Thus, we conclude in the human endometrium, there is significant ERβ2/βcx isoform expression and alterations in its levels could be involved in endometrial cancer progression.