Pre-neoplastic lesions associated with liver and colon responses to 1,2-dimethylhydrazine in an animal model of colorectal cancer

Abstract

Background: Oestrogen (ER) and androgen (AR) receptors play an important role in normal prostate development and are also implied in prostate cancer (PCa) development. Several studies suggested that physical activity may decrease the risk of PCa development and also changes sexual hormones and their receptors. This study aimed to evaluate the effects of physical exercise on ERα and AR expression in a rat model of chemically and hormonally-induced PCa. Material and methods: Fifty-five male Wistar Unilever rats of 12 weeks of age were randomly divided into four groups: control sedentary (n=10), control exercised (n=10), induced sedentary (n=15) and induced exercised (n=20). Animals from exercised groups started the exercise training in a treadmill (Treadmill Control LE 8710, Harvard Apparatus, USA), at the age of 8 weeks, for 35 weeks (5 days/week). The protocol for PCa induction started at 12 weeks of age and consisted of sequential administration of flutamide (50 mg/kg, TCI Chemicals), testosterone propionate (100 mg/kg, TCI Chemicals) and N-methyl-N-nitrosourea (30 mg/kg, Isopac®, Sigma Chemical Co.), followed by subcutaneous implants of crystalline testosterone. Animals were sacrificed at 61 weeks of age and a complete necropsy was performed. All experiments were approved by DGAV (no. 021326). Antibodies for Erα (1:500, clone 6F11, Novocastra) and AR (clone PG21, Merck Millipore) were used for the immunohistochemical study. The staining extension was evaluated in normal prostate tissue and in dorsolateral prostate lesions (hyperplasia, dysplasia, prostatic intraepithelial neoplasia (PIN) and microinvasive carcinoma) and assessed to five levels (0%, <25%, 25-50%, 50-75% and >75%), considering the extension of immunopositive tissue. Data was analysed with SPSS 25. Results: The normal prostate tissue and dorsolateral prostate lesions of animals from all groups were immunopositive for Erα and AR. However, the groups showed high immunopositivity for AR and low positivity for Erα (less than 25% in all groups) with similar values between both control and induced groups (p>0.05). The malignant lesions (PIN and microinvasive carcinoma) showed lower AR expression when compared with normal prostate tissue in all groups. Conclusions: As expected, the AR expression was lower in malignant lesions. Inversely to that reported in other studies, the exercise training did not modify the ERα and AR expression, which may be related to the duration and type of exercise performed.