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Estrogen Receptor-β as a Potential Target for Colon Cancer Prevention: Chemoprevention of Azoxymethane-Induced Colon Carcinogenesis by Raloxifene in F344 Rats

Authors' Affiliations: ¹ Department of Medicine, Hem-Onc Section, OU Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma and ² Division of Cancer Prevention, Chemopreventive Agent Development Research, Rockville, Maryland

Requests for reprints: Chinthalapally V. Rao, Department of Medicine, Hem-Onc Section, OU Cancer Institute, University of Oklahoma Health Sciences Center, 975 Northeast 10th Street, BRC Building II, Room 1203, Oklahoma City, OK 73104. Phone: 405-271-3224; Fax: 405-271-3225; E-mail: cv-rao{at}ouhsc.edu.

Raloxifene, selective estrogen receptor (ER) modulator, is not fully explored in colorectal cancer. In the present study we, (a) investigated the effect of raloxifene on ER-positive colon cancer HCT-116 cell growth, (b) assessed the relevance of ER-β in colon tumorigenesis, and (c) assessed the chemopreventive efficacy of raloxifene against azoxymethane (AOM)-induced colon carcinogenesis using aberrant crypt foci (ACF) as surrogate end point marker. HCT-116 cells treated with raloxifene showed a significant decrease in cell growth associated with a decrease in ER-β expression levels. AOM-induced colon adenocarcinoma showed significant up-regulation of ER-β expression at both the protein and mRNA levels compared with normal mucosa, suggesting that ER-β is positively associated with colon cancer. An assay using five different dietary dose levels (0.31, 0.62, 1.25, 2.5, or 5 ppm) of raloxifene for 6 weeks in male F344 rats found the maximum tolerated dose to be 5 ppm. To evaluate inhibitory properties of raloxifene on colonic ACF, 7-week-old rats were fed experimental diets containing 0, 0.625, 1.25, and 2.5 ppm of raloxifene. After 1 week, rats received s.c. injections of AOM, 15 mg/kg body weight, once weekly for 2 weeks. Rats continued to receive respective experimental diets and sacrificed 8 weeks after the last AOM treatment. Raloxifene given in the diet significantly inhibited AOM-induced total colonic ACF (31-40%; P < 0.001-0.0005) and multicrypt (four or more) aberrant foci (23-50%; P < 0.05-0.005) in F344 rats. Our findings suggest that ER-β acts as a colon tumor promoter and raloxifene as an antagonist to ER-β, providing protection against colon carcinogenesis.

Key Words: colon cancer • chemoprevention • raloxifene • ER-β • aberrant crypt foci

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