The Protective Effects of Estradiol on Sporadic and Inflammation-associated Colon Cancer
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Epidemiological studies suggest pre-menopausal women have a reduced risk for sporadic and inflammation-associated colon cancer compared to post-menopausal women and men. The studies presented herein aim to determine the protective mechanisms of estradiol (E2) during sporadic and inflammation-associated colonic carcinogenesis. When investigating the role of E2 and fish oil at the earliest stage of sporadic colon cancer development, E2 had no effect on DNA adduct formation while dietary fish oil significantly reduced DNA adduct formation. Contrarily, E2 significantly induced apoptosis of damaged colonocytes while fish oil was not protective. In an in vivo model of inflammation-associated colon carcinogenesis with E2 administered following induction of DNA damage and initiation of inflammation, E2 treatment was associated with decreased colon tumor size and number in wild type (WT) but not estrogen receptor (ER) β knockout (ERβKO) mice. Interestingly, apoptosis was reduced and proliferation increased by E2 in these tumors in WT mice. This may be due to the altered ER expression in these tissues as the tumors developed, with ERβ expression decreasing concomitantly with ERα expression increasing. Contrary to the protective effect of E2 on inflammation-associated colon tumor formation, which was dependent on ERβ, during acute inflammation in the colon E2 was protective against inflammation in both WT and ERβKO mice and injury in ERβKO mice. The protection against inflammation is likely due to the reduction of pro-inflammatory cytokine expression by E2. Apoptosis and proliferation were decreased and increased in the proximal and distal colon respectively in ERβKO mice. In vitro studies further elucidated the roles of ERα and ERβ in colonocytes. E2 and ERβ, but not ERα, specific agonists reduced cell number and induce apoptosis in nonmalignant colonocytes. This effect was lost in the presence of mutated p53. In ERα overexpressed nonmalignant colonocytes, E2 had no effect on cell number while ERβ agonist and ERα agonists decreased and increased cell number respectively. These studies suggest that E2 is protective in the colon and ERβ is required for protection against carcinogenesis but not protection against inflammation. Additionally, the protection against colon carcinogenesis is likely p53 mediated.
Armstrong, Cameron Michelle (2013). The Protective Effects of Estradiol on Sporadic and Inflammation-associated Colon Cancer. Doctoral dissertation, Texas A & M University. Available electronically from