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.