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CHEMOPREVENTIVE EFFECT OF ERbeta SPECIFIC AGONIST ON INTESTINAL TUMORIGENESIS IN APCMIN/+ MICE
V Giroux, G Bernatchez, J Carrier
Medicine and Anatomy and Cell Biology, University of Sherbrooke, QC
Different evidences suggest that estrogen replacement therapy reduces colon cancer risk in postmenopausal women. The estrogen receptor beta (ERbeta) is thought to be the principal mediator of estrogen effect in colonocytes. Recent studies of our team showed that ERbeta deficiency in APCMin/+ mice enhances intestinal tumorigenesis and epithelial proliferation and that a positive regulation of TGFbeta pathway by estrogen in colon epithelial cells could contribute to the anti-proliferative effect of ERbeta. The aim of this study was to investigate the effects of ERbeta agonist treatment on intestinal tumorigenesis in APCMin/+ male and female mice and on TGFbeta signaling pathway. Weaned APCMin/+ mice were injected 3-times per week for 12 weeks with vehicle or the ERbeta specific agonist, diarylpropionitrile (DPN, 5mg/kg). The numbers of intestinal polyps, epithelial proliferation and apoptosis as well as components of the TGFbeta pathway were studied.
RESULTS: DPN treatment resulted in significant reduction of small intestinal polyp numbers in both APCMin/+ male (40%, p=0,002) and female (36% reduction, p=0,03). Furthermore, the mean diameter of polyps was lower in DPN- vs vehicle-treated male (13%, p=0,03). The number and the incidence of polyps in the colon were not changed by DPN administration. BrdU incorporation assay revealed a consistent reduction in epithelial cell proliferation by DPN treatment in the jejunum of male (41%) and female (37%) mice (p<0,0001) as well as in the colon of male (45%) and female (48%) mice (p<0,0001). In addition, there were a 77% increase of cleaved caspase 3, an apoptosis marker, in colon epithelial cells from DPN- vs vehicle-treated APCMin/+ mice (p=0,01). Because our previous experiments suggested an implication of TGFbeta pathway in the protective role of estrogen on colorectal cancer, we studied the effect of DPN on various component of the TGFbeta pathway in the colon. We observed higher TGFbeta1 (32%, p=0,03) and TGFbeta3 transcripts (264%, p=0,04) in DPN- vs vehicle-treated APCMin/+ mice. Interestingly, we observed an increase of 24% in levels of phosphorylated Smad2/3 in DPN- vs vehicle-treated APCMin/+ mice (p=0,05) and an increase of 38% for gene target expression, p27 (p=0,02).
CONCLUSION: Our results demonstrate that DPN treatment reduced intestinal tumorigenesis in association with lower epithelial proliferation and higher colonocyte apoptosis. Furthermore, we suggest that positive regulation of TGFbeta pathway by ERbeta activation could explain the protective role of estrogen on intestinal tumor development.