Comparative Evaluation of Estrogen and Progesterone Receptor Expression With Connexins 26 and 43 in Endometrial Cancer

Abstract

Progression of numerous neoplasms could involve alterations of gap junction channels composed of connexins (Cxs). Disorders of expression and cellular displacement of Cxs were also found in endometrial cancer. Gap junctional intercellular communication can be regulated by wide array of agents, for instance, growth factors, oncogenes, and steroid hormones. Nevertheless, expressions of Cxs and progesterone receptor (PR) were not compared in human tissues. This study focused on assessment of expression of estrogen receptor alpha (ERalpha) and PRs in relation to the expression of Cx26 and Cx43 in 88 cases of endometrial cancer and analysis of these proteins' expression in comparison with anatomoclinical features. Positive ERalpha and PR nuclear staining was present in 66 (75%) and 60 (68.2%) of all studied tumors, respectively. Positive correlation was found between expression of PR and histopathologic type of tumor (P = 0.026), and negative correlation was drawn with grading (G) (P = 0.002). There were positive reactions to Cx26 and Cx43 of mainly cytoplasmic location in 60 (68.2%) and 66 (75%) of studied cancers, respectively. Progesterone receptor expression correlated negatively with Cx26 in endometrial cancers (P = 0.016, r = -0.256). Moreover, ERalpha expression positively correlated with PR expression (P < 0.001, r = 0.678). On the ground of our findings, disorders of Cx expression and altered distribution pattern occur during endometrial carcinogenesis, and it seems that PR could participate in this fact. Loss of functional gap junctions may occur because of the aberrant expression and localization of Cx26 and Cx43 in endometrial cancer.

Eventual proapoptotic or anti-apoptotic impact of aberrantly expressed Cx43 and Cx26 can depend on ER-alpha overexpression in human endometrioid adenocarcinoma

“…Most human endometrial adenocarcinomas express progesterone receptor and estrogen receptor alpha, so the relations of connexins with PgR and ER could turn out to be crucial in the development of this cancer [2]. However, there were no relationship between Cx26 and ER or between Cx43 and hormonal receptors in our previous study [2]. Phosphorylation of Cx43 causes deregulation of communication via gap junction channels in endometrium [4].…”

“…A Cx26 stimulating property was found in case of the phytoestrogen, genistein [7]. In our previous study only progesterone receptor expression was found to associate with Cx26 and grading in the manner of negative correlation in endometrial cancers, while Cx26 positively correlated with tumor stage [2,8]. In this perspective an eventual impact of connexins on apoptosis is of great importance.…”

“…Estrogen receptor (ER) and progesterone receptor (PgR) accumulations lead to impairment of gap junctional intercellular communication in endometrial cancer what was partially confirmed by negative correlation of PgR expression and Cx26 in endometrial cancers [2]. Expression of anther one connexin, Cx43, decreased with poor differentiation of endometrial cancer [3].…”

“…17beta-estradiol via ERalpha mediates suppression of Cx26 and Cx32 expressions and results in the loss of GJIC in Ishikawa human endometrial cancer cell line (stable clone IK-ER1 overexpressing ER-alpha) [5]. Most human endometrial adenocarcinomas express progesterone receptor and estrogen receptor alpha, so the relations of connexins with PgR and ER could turn out to be crucial in the development of this cancer [2]. However, there were no relationship between Cx26 and ER or between Cx43 and hormonal receptors in our previous study [2].…”

Association of STAT3 with Cx26 and Cx43 in human uterine endometrioid adenocarcinoma

“…Standard immunohistochemical procedure for STAT3, Cx43, Cx26 ER and PgR was performed in endometrioid adenocarcimonas according to previously described protocols (10,(12)(13). Briefly, endogenous peroxidase activity was blocked with 60 sec treatment of slides 3% hydrogen peroxide (Santa Cruz Biotechnology, Inc. Santa Cruz, CA, USA, and then the slides were exposed to 1.5% normal blocking serum (Dako) for 90 min to inhibit unspecific binding reaction.…”