4-hydroxyestradiol and Microsatellite-Instability

Catechol estrogens, such as 4-hydroxyestradiol (4-OHE2), are estrogen metabolites that form DNA adducts and may induce mutations and subsequent cell transformation in mammary cells; however, little is known about their roles in endometrial carcinogenesis. Furthermore, it remains unclear whether 4-OHE2 is able to induce DNA damage on specific genes involved in carcinogenesis or a 'pro'-mutation status such as microsatellite instability (MSI). Therefore, we modified terminal transferase-dependent PCR by the application of a capillary sequencer to detect DNA damage at the single base level. Using this method, we demonstrated that 4-OHE2 directly induced DNA damage on codon 130/131 in exon 5 of PTEN, which is a mutation hot spot for PTEN in endometrial carcinoma. Whereas, both estradiol and 4-OHE2 treatment did not affect MSI status in immortalized endometrial glandular cells. 4-OHE2 might contribute to endometrial carcinogenesis by inducing PTEN mutation on codon 130/131.

Topics: Base Sequence; Cell Line, Transformed; Cell Line, Tumor; Cell Transformation, Neoplastic; Codon; DNA Adducts; DNA Damage; DNA Mutational Analysis; Endometrium; Epithelial Cells; Estrogens, Catechol; Exons; Female; Gene Expression; Humans; Microsatellite Instability; Molecular Sequence Data; Point Mutation; Polymerase Chain Reaction; PTEN Phosphohydrolase