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

Estrogen receptor beta (ER beta) has five carboxyl-terminal (C-terminal) isoforms derived from alternative splicing. ER beta 1 is the wild-type receptor whereas ER beta 2/beta cx 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 ER alpha. The objective of this study was to analyze the expression of ER beta 1 and ER beta 2/beta cx 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 ER beta 2/beta cx protein, a polyclonal antibody was raised to its unique C-terminus, characterized, and used in immunohistochemistry. The two ER beta isoforms are expressed in the proliferative and secretory phase endometrium with no significant change in their relative levels. The levels of the ER beta 1 isoform. were lower as compared to the levels of ER beta 2 in all the groups studied. Expression of ER beta 2/beta cx was decreased in endometrioid carcinoma as compared to proliferative endometrium (P < 0.01). A significant decrease of the ER beta 2/ER beta cx transcript was observed with higher grade tumors (P = 0.041). Progesterone receptor (PR) expression was not influenced by either of the ER beta isoforms which was observed by logistic regression analysis in all the groups. The coexpression of ER beta 2/beta cx with ER alpha did not affect PR levels (logistic regression analysis). Thus, we conclude in the human endometrium, there is significant ER beta 2/beta cx isoform expression and alterations in its levels could be involved in endometrial cancer progression.