Immunohistochemical characterization of differentiation-associated transcription factors,tumor suppressor genes,and mismatch repair genes in rabbit uterine adenocarcinoma

The development of human uterine cancer is a complex process involving the abnormal expression of tumor suppressors, such as PTEN, ARID1A, and TP53; mismatch repair protein MSH6; and transcription factors, such as PAX2 and PAX8. The functional changes that lead to uterine adenocarcinoma in pet rabbits are not fully understood despite the frequent occurrence of this condition in the species. Thus, an immunohistochemical analysis was performed to visualize the protein expression pattern of carcinogenesis-related molecules in surgical biopsy specimens from 56 uterine adenocarcinomas and 8 uteruses without significant lesions in pet rabbits. Seventy percent of the adenocarcinomas were positive for estrogen receptor (ER), 7% were positive for TP53, and there was a decreased expression in comparison to control uterine epithelium for PAX2 in 54%, for PAX8 in 73%, for ARID1A in 68%, and for MSH6 in 48% of the tumors. TP53 expression was not observed in control uterine tissues. There was a significant negative correlation between nuclear ER and PAX2 immunolabeling in uterine adenocarcinomas. Heat map analysis classified samples into 4 clusters, which revealed that 1 PAX2-positive group had a higher presence of papillary-type uterine adenocarcinomas and a lower prevalence of tubular/solid types compared with the 2 PAX2-negative groups. This study demonstrated that the immunohistochemical phenotype of rabbit uterine adenocarcinoma is comparable to that of human endometrial carcinomas, suggesting the potential for similar oncogenic mechanisms that might prove useful for translational medicine research.