Influence of Estradiol and Phytoestrogens on Colitis and Colon Cancer

Estrogen is a female sex hormone that has a variety of biologic actions via modulation of gene expression through estrogen receptors (ERs). The protective effect of estradiol (E2) and estrogen signaling in colon cancer has been demonstrated in epidemiological and clinical data as well as animal experiments. The overall aim of this series of studies is to determine the protective mechanism of estrogen signaling activated by E2 and phytoestrogens on colitis and colon cancer. First, the estrogenic effect of novel phytoestrogens, trigonelline (Trig) and 3,3-diindolylmethane (DIM) was determined in non-malignant colonocytes (YAMCs). Both molecules decreased cell growth of YAMCs, but their mechanisms of action were distinct from E2. Trig increased apoptosis by functional ERs without direct binding to ERs while DIM altered the expression of target genes of ERs via increased ER transcriptional activity. These data suggest that phytoestrogens could activate estrogen signaling through unique mechanisms. Second, the protective effect of estrogen signaling on colitis and colitis associated colon cancer (CAC) was demonstrated in vitro and in vivo. In the in vitro study, IL-6 induced cell growth was observed, and E2 and genistein (GEN) treatment inhibited IL-6 actions via an increase of apoptosis and modulation of gene expression related to estrogen signaling. In the in vivo colitis experiment, chronic inflammation damaged the colon, but E2 treatment increased the recovery of the damaged colon via an increase of cell proliferation with modulation of cytokines. However, GEN treatment exacerbated the damage on chronic inflammation. In the CAC model, E2 and GEN treatment suppressed the formation of aberrant crypt foci (ACF), premalignant lesions. These data suggest that E2 protects the colon and colon epithelial cells, and the protective mechanism of estrogen signaling differs depending on the type of injury and local conditions. Lastly, the interaction of estrogen signaling and the p53 pathway was studied using intestinal epithelial cell-specific p53 knockout mice (Tp53^ΔIEC). The protective effect of E2 in Tp53^ΔIEC mice was observed, suggesting that the suppression of ACF by estrogen signaling is partially independent of the p53 pathway. Overall, estrogen signaling has a protective property against colitis and colon cancer but the protective mechanism of estrogen signaling could be changed from apoptosis to proliferation depending on the condition of the colon. In addition, each phytoestrogen has a distinct and unique way of influencing the colon. These data help clarify the role and the mechanism of estrogen signaling on colon cancer