Up-regulation and nuclear localization of beta-catenin in endometrial carcinoma in response to progesterone therapy.
Ovarian hormones are considered to be capable of regulating expression of beta-catenins. A possible role of beta-catenin in alteration of cell morphology has been proposed, but little is known about beta-catenin expression during changes in the tumor morphology of endometrial carcinomas induced by progesterone therapy. To clarify changes in expression of beta-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 beta-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 beta-catenin gene mutation (A32V), cytoplasmic beta-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 beta-catenin expression in endometrial tumors. Moreover, nuclear beta-catenin accumulation, like gene abnormalities, is associated with the alteration of tumor morphology due to progesterone, indicating that beta-catenin may be a clinically useful marker of hormone therapeutic effects.
Saegusa
Makoto
M
Department of Pathology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555. msaegusa@med.kitasato-u.ac.jp
Hamano
Mieko
M
Kuwata
Takeshi
T
Yoshida
Tsutomu
T
Hashimura
Miki
M
Akino
Fumiyuki
F
Watanabe
Jun
J
Kuramoto
Hiroyuki
H
Okayasu
Isao
I
D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D019943:Amino Acid Substitution; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers; D018269:Carcinoma, Endometrioid / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017930:Genes, Reporter; D006801:Humans; D006965:Hyperplasia; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology* / Q000627:therapeutic use; D008875:Middle Aged; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011980:Receptors, Progesterone / Q000096:biosynthesis / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000032:analysis; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051176:beta Catenin
D018931:Antineoplastic Agents, Hormonal; D015415:Biomarkers; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D011980:Receptors, Progesterone; D011993:Recombinant Fusion Proteins; D015534:Trans-Activators; D051176:beta Catenin; D017258:Medroxyprogesterone Acetate; D008156:Luciferases