Dietary retinoic acid supplementation stimulates intestinal tumour formation and growth in multiple intestinal neoplasia (Min)/+ mice.
Chemopreventive activity by retinoic acid (RA) has been demonstrated previously in rat colon. The spontaneous tumourigenesis in the Min/+ mouse, which harbours a germline mutation in the tumour suppressor gene adenomatous polyposis coli (Apc), is characterized by inactivation of Apc, nuclear accumulation of beta-catenin and the enhanced expression of specific genes activated by T cell factor (TCF)/beta-catenin signalling. Recently it was reported that beta-catenin interacts with retinoic acid receptor in a retinoid-dependent manner, reducing beta-catenin/TCF regulated transcription. Our hypothesis was therefore that dietary supplementation with all-trans RA may inhibit the Apc-driven tumourigenesis in Min/+ mice. Surprisingly, in two different experiments the results showed that dietary RA significantly stimulated both the formation and growth of small intestinal tumours. In the first experiment Min/+ mice were exposed to 50 mg 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine/kg bodyweight at day 3-6 after birth and then treated with 50 mg/kg dietary RA in 1-3 weeks from the age of 2 weeks. In the second experiment the mice were not treated with carcinogen, and the diet was supplemented with 5 or 10 mg/kg RA from the age of 4 weeks until termination of the experiment at 11 weeks. Immunohistochemical studies revealed no differences in beta-catenin, cyclin D1 or proliferating cell nuclear antigen staining following RA treatment. There was no intestinal toxicity in mice fed 10 mg/kg RA, indicating that the increased tumourigenesis in Min/+ mice is a specific effect of all-trans RA.
D000818:Animals; D001835:Body Weight; D019938:Cyclin D1 / Q000032:analysis; D003598:Cytoskeletal Proteins / Q000032:analysis; D019587:Dietary Supplements; D005260:Female; D017491:Genes, APC; D018095:Germ-Line Mutation; D007093:Imidazoles / Q000633:toxicity; D007414:Intestinal Neoplasms / Q000139:chemically induced* / Q000737:chemistry / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D015534:Trans-Activators / Q000032:analysis; D014212:Tretinoin / Q000633:toxicity*; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D007093:Imidazoles; D018809:Proliferating Cell Nuclear Antigen; D015534:Trans-Activators; D051176:beta Catenin; D019938:Cyclin D1; D014212:Tretinoin; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine