Nuclear localization of ?-catenin in normal and carcinogenic endometrium

Abstract

We have previously shown that the connexin (Cx) 26 and 32 genes are expressed during the secretory phase of the human endometrium and that their expression is downregulated during the proliferative phase, suggesting a role for intercellular transduction in cell growth control in human endometrium. To further study the possible role of cell-to-cell interaction in growth regulation, we immunohistochemically analyzed 80 endometrial samples (30 of normal endometrium, 20 of endometrial hyperplasia, and 30 of endometrial cancer) for the expression of E-cadherin; alpha-, beta-, and gamma-catenin; adenomatous polyposis coli (APC) protein, and sex-steroid hormone receptors at three points in the cells: the cell-to-cell border, the cytoplasm, and the nucleus. In this study, moderate or strong staining of beta-catenin in the nuclei was observed in 60.0% of endometrial hyperplasia samples and 30.0% of endometrial cancer samples, although the beta-catenin gene was mutated in only two of the nine samples that showed the intensive nuclear staining. Western blotting analysis showed that the samples that had intense nuclear staining of beta-catenin had much higher expression of beta-catenin than the samples that did not have nuclear staining. Furthermore, normal endometrium showed nuclear localization, especially in the mid- and late-proliferative and early-secreting phases of the menstrual cycle. The results suggest that the nuclear localization of beta-catenin observed in endometrial hyperplasia and endometrial cancer, as in other tumors, implies that beta-catenin/Wnt-1 signal transduction is highly activated in carcinogenesis of the endometrium as well as in normal physiological conditions.

Wnt-signalling pathway in ovarian epithelial tumours: increased expression of β-catenin and GSK3β

“…In the current study, cytoplasmic and cell border staining of the overlying epithelium (OSE) was present, while nuclear staining was absent. Nuclear APC staining has been described in the uterus using the same antibody as in this study (Nei et al, 1999). We believe that APC was not truncated in the normal ovary or in the normal colon sample since the immunoblot demonstrated a band at the expected size of 312 kDa (Smith et al, 1993).…”

“…Others, as well as the results of this study, have revealed that bcatenin is localised at the cell borders and not in the nucleus of normal OSE or OSE lining the inclusion cysts (Davies et al, 1998). However, nuclear b-catenin has been described in normal cells of other organs such as the endometrium of the uterus (Nei et al, 1999). Mutations in the b-catenin gene are infrequent in ovarian carcinoma and interestingly only described in the endometrioid type of epithelial ovarian tumours (Palacios and Gamallo, 1998;Wright et al, 1999).…”

Distinct sets of gene alterations in endometrial carcinoma implicate alternate modes of tumorigenesis

“…Nei et al found that strong nuclear staining of ␤-catenin was more frequent in endometrial hyperplasia than in endometrial carcinoma samples, suggesting a role in the early development of this tumor type. 49 Their study did not show any correlation between the presence of hyperplasia and expression of ER, suggesting that the CTNNB1/wnt-1 signaling pathway is activated irrespective of ER stimulation. In another study, two endometrial tumors with ␤-catenin mutations had adjacent hyperplasia with wild0type ␤-catenin, suggesting a role of ␤-catenin activation in the transition from benign to malignant phase, though not necessarily a gatekeeper-type event, in endometrial tumorigenesis.…”

Expression of cell cycle regulatory proteins in endometrial adenocarcinoma: variations in conventional tumor areas and in microcystic, elongated and fragmented glands

“…[12][13][14]22,23 Abnormalities of b-catenin have also been shown in a significant proportion of endometrial neoplasms. 3,5 Mutations have been recorded in 13-31% cases and appear more common in lowgrade endometrioid adenocarcinomas, [31][32][33][34][35][36] whereas an abnormal immunolocalization in the form of reduced membrane staining with diffuse cytoplasmic and/or nuclear staining has been recorded in 25-76% cases. [34][35][36][37][38][39] Most b-catenin mutations lead to decreased protein degradation and are associated with altered (usually nuclear) immunoreactivity.…”

“…3,5 Mutations have been recorded in 13-31% cases and appear more common in lowgrade endometrioid adenocarcinomas, [31][32][33][34][35][36] whereas an abnormal immunolocalization in the form of reduced membrane staining with diffuse cytoplasmic and/or nuclear staining has been recorded in 25-76% cases. [34][35][36][37][38][39] Most b-catenin mutations lead to decreased protein degradation and are associated with altered (usually nuclear) immunoreactivity. 32,35 However, the converse is not always true as dysregulation of many other factors can lead to the abnormal localization of b-catenin, reflecting the multiple pathways that control the distribution and metabolism of this protein.…”