Carcinogenic potential of fluorinated estrogens in mammary tumorigenesis

Fluorination preventing metabolic hydroxylation of 17β-estradiol (E₂) was applied to investigate the mechanisms underlying estrogen-induced carcinogenesis. Either 2-fluoro-17β-estradiol (2-FE₂) or 4-fluoro-17β-estradiol (4-FE₂) was administered subcutaneously for 52 weeks to August Copenhagen Irish (ACI) rats, the preferred animal model for human breast cancer. 4-FE₂ induced frequent mammary tumors whereas 2-FE₂ did not. The cumulative incidence of mammary tumors in rats treated with 4-FE₂ was comparable to that observed with E₂. The carcinogenic results were supported by histological examination of mammary glands of fluorinated estrogen-treated ACI rats. To evaluate the estrogenic potential of the fluorinated estrogens, 2-FE₂ or 4-FE₂ was administrated subcutaneously to ovariectomized rats. Both 4-FE₂ and 2-FE₂ showed high uterotrophic potency. Our results indicate that estrogenic potential may not be the sole factor driving mammary tumorigenesis. Since fluorination inhibits metabolic hydroxylation of E₂ at the substituted position, the carcinogenic effect may occur through the metabolic activation of 2-hydroxylated E₂, in combination with the compound's estrogenic potency.