Journal Article

Dietary retinoic acid supplementation stimulates intestinal tumour formation and growth in multiple intestinal neoplasia (<i>Min</i>)/+ mice

Linda Møllersen, Jan Erik Paulsen, Hege Benedikte Ølstørn, Helle Katrine Knutsen and Jan Alexander

in Carcinogenesis

Volume 25, issue 1, pages 149-153
Published in print January 2004 | ISSN: 0143-3334
Published online January 2004 | e-ISSN: 1460-2180 | DOI:
Dietary retinoic acid supplementation stimulates intestinal tumour formation and growth in multiple intestinal neoplasia (Min)/+ mice

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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 β-catenin and the enhanced expression of specific genes activated by T cell factor (TCF)/β-catenin signalling. Recently it was reported that β-catenin interacts with retinoic acid receptor in a retinoid-dependent manner, reducing β-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 β-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.

Keywords: ACF, aberrant crypt foci; AOM, azoxymethane; APC/Apc, adenomatous polyposis coli; LEF, lymphoid enhancer factor; Min, multiple intestinal neoplasia; PCNA, proliferating cell nuclear antigen; PhIP, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; RA, retinoic acid; RAR, retinoic acid receptor; RXR, retinoid X receptor; TCF, T cell factor

Journal Article.  4490 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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