Clinical and animal studies have shown a strong link between estrogen status in women and decreased risk of colon cancer. However, little research has been done into the mechanism of protection that estrogen provides. Our laboratory has demonstrated that estradiol (E₂) inhibits the development of pre-neoplastic lesions through an estrogen receptor β (ERβ) mediated mechanism in mice. Our data also suggest that the primary protective role of E₂ treatment is increased apoptosis in non-malignant colonocytes that are damaged and at risk of becoming cancerous. The p53 protein plays a crucial role in the cellular response to stress by inducing cell cycle arrest, DNA repair mechanisms, and/or apoptosis. Due to the observed induction of apoptosis in response to E₂, we are investigating the role of p53 in this chemo-protective mechanism. E₂ suppressed growth of young adult mouse colonocytes (YAMCs) by inducing apoptosis and these physiological responses were completely lost in YAMCs lacking a functional p53 protein. Western blot analysis demonstrated increases in p53 protein levels in YAMCs after treatment with E₂ likely due to protein stabilization. E₂ was shown to enhance the transcriptional activity of p53, resulting in up-regulation of pro-apoptotic p53 target genes (Bax, Noxa, and PUMA). Finally, repair of DNA double stranded breaks was shown to be increased by E₂ treatment. Collectively, these data are the first to demonstrate that p53 is a primary mediator of the protective actions of E₂ in the colon.
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