Molecular classification of spontaneous endometrial adenocarcinomas in BDII rats

Abstract

Female rats of the BDII/Han inbred strain are prone to spontaneously develop endometrial carcinomas (EC) that in cell biology and pathogenesis are very similar to those of human. Human EC are classified into two major groups: Type I displays endometroid histology, is hormone-dependent, and characterized by frequent microsatellite instability and PTEN, K-RAS, and CTNNB1 (b-Catenin) mutations; Type II shows non-endometrioid histology, is hormone-unrelated, displays recurrent TP53 mutation, CDKN2A (P16) inactivation, over-expression of ERBB2 (Her2/neu), and reduced CDH1 (Cadherin 1 or E-Cadherin) expression. However, many human EC have overlapping clinical, morphologic, immunohistochemical, and molecular features of types I and II. The EC developed in BDII rats can be related to type I tumors, since they are hormone-related and histologically from endometrioid type. Here, we combined gene sequencing (Pten, Ifr1, and Ctnnb1) and real-time gene expression analysis (Pten, Cdh1, P16, Erbb2, Ctnnb1, Tp53, and Irf1) to further characterize molecular alterations in this tumor model with respect to different subtypes of EC in humans. No mutation in Pten and Ctnnb1 was detected, whereas three tumors displayed sequence aberrations of the Irf1 gene. Significant down regulation of Pten, Cdh1, p16, Erbb2, and Ctnnb1 gene products was found in the tumors. In conclusion, our data suggest that molecular features of spontaneous EC in BDII rats can be related to higher-grade human type I tumors and thus, this model represents an excellent experimental tool for research on this malignancy in human.

Expression patterns of Phf5a/PHF5A and Gja1/GJA1 in rat and human endometrial cancer

“…Therefore, in studies of complex disease and as a complement to studies in human, model organisms such as inbred rat strains are often used. The use of rat models is preferable since rat has similarities in pathogenesis and histopathological properties to those of human [2,4]. In the EAC susceptible BDII rat strain, more than 90% of the virgin females develop tumors spontaneously during their lifetime.…”

Involvements of Estrogen Receptor, Proliferating Cell Nuclear Antigen and p53 in Endometrial Adenocarcinoma Development in Donryu Rats

“…The present study and our previous studies described in the introduction indicate that the endometrial adenocarcinomas in the Donryu rat strain have many similarities to type I, endometrioid adenocarcinoma in women. Samuelson et al reported that spontaneous endometrial adenocarcinomas in BDII rats are also similar to type I tumors in women 38 . On the other hand, a possibility might exist that the poorly differentiated types in the present study might be biologically different from well-differentiated adenocarcinomas, because of the similarity of the p53 profile in the poorly-differentiated adenocarcinomas in rats to that of type II carcinomas in women.…”

Uterine Carcinomas in Tetrabromobisphenol A–exposed Wistar Han Rats Harbor Increased Tp53 Mutations and Mimic High-grade Type I Endometrial Carcinomas in Women

“…Interestingly, the BDII Han rat model develops a high rate of spontaneous uterine carcinomas (~90%) which, based on molecular features, have also been classified as similar to high-grade Type I ECs in women (Adamovic et al ., 2008; Behboudi et al ., 2001; Nordlander et al ., 2005; Samuelson et al ., 2009). They have an early onset, endometrioid differentiation, and are estrogen responsive, but have high rates of Tp53 mutation, similar to the uterine carcinomas observed in TBBPA-exposed Wistar Han rats in this study.…”