Estrogen receptor-beta as a potential target for colon cancer prevention: chemoprevention of azoxymethane-induced colon carcinogenesis by raloxifene in F344 rats.
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.
Janakiram
Naveena B
NB
Department of Medicine, Hem-Onc Section, OU Cancer Institute, University of Oklahoma Health Sciences Center, 975 Northeast 10th Street, Oklahoma City, OK 73104, USA.
Steele
Vernon E
VE
Rao
Chinthalapally V
CV
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
D000970:Antineoplastic Agents; D002273:Carcinogens; D047629:Estrogen Receptor beta; D020849:Raloxifene Hydrochloride; D001397:Azoxymethane