title: Estrogen receptor-beta as a potential target for colon cancer prevention: chemoprevention of azoxymethane-induced colon carcinogenesis by raloxifene in F344 rats.
abstract: 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-beta 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-beta expression levels. AOM-induced colon adenocarcinoma showed significant up-regulation of ER-beta expression at both the protein and mRNA levels compared with normal mucosa, suggesting that ER-beta 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-beta acts as a colon tumor promoter and raloxifene as an antagonist to ER-beta, providing protection against colon carcinogenesis.
authors.affiliation: Department of Medicine, Hem-Onc Section, OU Cancer Institute, University of Oklahoma Health Sciences Center, 975 Northeast 10th Street, Oklahoma City, OK 73104, USA.
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.forename: Vernon E
authors.initials: VE
authors.lastname: Steele
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001397:Azoxymethane / Q000633:toxicity; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D018890:Chemoprevention; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000517:prevention & control*; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage*; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000970:Antineoplastic Agents; D002273:Carcinogens; D047629:Estrogen Receptor beta; D020849:Raloxifene Hydrochloride; D001397:Azoxymethane