Histological evaluation of endometrial cancer in BDII/Hans rats and a pilot study of the impact of liraglutide and calorie restriction on tumour incidence and type

Introduction: Female BDII/Han rats represent a model of spontaneous endometrial cancer (EC). Although predominantly endometrioid in nature, various aspects of the histology of the tumours developed in the model have not been the subject of systematic examination. Endometrioid endometrial cancer (EC1) in humans is associated with obesity and insulin resistance, and accordingly weight loss interventions are associated with a reduction in the incidence and progression of this cancer. Through the promotion of satiety and attendant reductions in food intake, Glucagon-like 1 peptide (GLP-1) based therapies (such as the stable synthetic analogue Liraglutide), are an effective therapy for obesity and may reduce the incidence and arrest the progression of early-stage EC1. The aims of this pilot study were to compare tumour incidence and type in the BDII/Han rat model when rats were maintained on ad libitum food intake versus treatment with liraglutide therapy in combination with 50% caloric restriction. Methodology: Twelve-month-old BDII/Han rats (n=38) were randomised to either ad libitum access to a standard rodent chow diet (STD n=17) or Liraglutide (1mg/kg/d) therapy plus 50% caloric restriction (LIR n=21). After three months, animals were euthanised, and uterine horns were retrieved to record tumour incidence and assess both tumour type and grade. The oestrus cycle stage was established via assessment of ovarian and endometrial histology. Results: The LIR regimen resulted in 15% weight loss. Tumour incidence was 58% (10 of 17) in STD and 19% (4 of 21) in the LIR group (p = 0.0184). In the STD group, 7 of the 8 tumours assessed histologically were classifiable as EC1, with one animal developing a serous-type tumour (EC2). Conversely, all four tumours in the LIR-diet group were of the EC2 type, as confirmed by p16 immunohistochemistry, and were immune poor/excluded. Upon assessment of ovarian and endometrial histology with respect to the oestrus cycle stage, the residual tumour burden in LIR rats was frequently associated with oestrus cycle arrest; specifically in dioestrus (64%) and proestrus (29.4%). Follicular atresia was frequently observed. Conclusion: In this pilot study, liraglutide in combination with dietary restriction largely prevented the development of EC1-like disease in BDII/Han rats. Evidence suggests that the treatment also selected for the development of serous type, hormone-independent cancer in a smaller number of animals.