Up-regulation and nuclear localization of β-catenin in endometrial carcinoma in response to progesterone therapy

Abstract

Ovarian hormones are considered to be capable of regulating expression of β-catenins. A possible role of β-catenin in alteration of cell morphology has been proposed, but little is known about β-catenin expression during changes in the tumor morphology of endometrial carcinomas induced by progesterone therapy. To clarify changes in expression of β-catenin and their relation to morphological alteration, expression of hormone receptors and several cell kinetic markers, sequential biopsy and hysterectomy specimens of 23 endometrial carcinoma and 6 complex hyperplasia with atypia (atypical hyperplasia) cases receiving progesterone therapy were investigated. In vitro assay was also conducted using two endometrial carcinoma cell lines (HEC265 and Ishikawa) expressing progesterone receptors (PRs). An increase of nuclear β-catenin accumulation was evident during progesterone therapy in endometrial carcinomas and atypical hyperplasias. The nuclear labeling indices were significantly associated with gene mutations and alteration in morphological features in response to progesterone, independently of the status of Ki-67, p21WAF1 and p27Kip1, and hormone receptors. In HEC265 having a β-catenin gene mutation (A32V), cytoplasmic β-catenin levels were elevated by progesterone treatment, linked to down-regulation of PR expression, but such changes were relatively minor in Ishikawa without the gene alterations. These findings demonstrate a possible role of progesterone in regulation of β-catenin expression in endometrial tumors. Moreover, nuclear β-catenin accumulation, like gene abnormalities, is associated with the alteration of tumor morphology due to progesterone, indicating that β-catenin may be a clinically useful marker of hormone therapeutic effects.