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4-hydroxyestradiol and 16α-hydroxyestrone increasing proliferation and decreasing apoptosis in a manner similar to estradiol; however, these effects were achieved only at concentrations 10-fold higher than estradiol (39). In contrast, 2-hydroxyestradiol did not have substantial proliferative or antiapoptotic effects

In our study, the associations with both 2-hydroxyestrone and 16α-hydroxyestrone were nonsignificantly inverse and we did not observe a consistent trend or significant associations between the 2-hydroxyestrone:16α-hydroxyestrone ratio and breast cancer risk

Ratios of the 3 hydroxylation pathways were not significantly associated with risk although the 2:16-pathway and 4:16-pathway ratios were suggestively inversely associated

a significant inverse association with the ratio of parent estrogens to estrogen metabolites

several potentially estrogenic and genotoxic mechanisms

Estrogen metabolites also can be genotoxic

Catechol estrogens can be oxidized into quinones and induce DNA damage directly through the formation of DNA adducts, or indirectly via redox cycling and generation of reactive oxygen species

the oxidized forms of the catechol estrogens differ in their ability to damage DNA through adducts, with oxidized 2-catechols forming stable and reversible DNA adducts and oxidized 4-catechols forming unstable adducts, which lead to depurination and mutations

2- and 4-catechols have been shown to produce reactive oxygen species and induce oxidative DNA damage

act independently from the ER

16α-Hydroxyestrone also may be genotoxic

While the catechol estrogens have estrogenic and genotoxic potential, the methylated catechol estrogens, which are catechol estrogens with one hydroxyl group methylated, have been hypothesized to lower the risk of breast cancer

The suggested mechanisms are indirect, by decreasing circulating levels of catechol estrogens and thereby the opportunity for catechols to exert genotoxic or proliferative effects, or direct, by inhibiting tumor growth and inducing apoptosis

the balance between phase I (oxidation) and phase II (methylation) metabolism of estrogen may be important in hormonally related cancer development.

Despite the estrogenic and genotoxic potential of many of the estrogen metabolites, we only observed a significantly increased breast cancer risk with one estrogen metabolite, 17-epiestriol, which has particularly strong estrogenic activity and binds to both ERα and ERβ with an affinity comparable with estradiol

On the whole, prospective epidemiological data do not support the hypothesis that the 2-hydroxyestrogen pathway is protective, and the 16α-hydroxyestrogen pathway harmful, in hormone-dependent cancers

Both 2- and 4-hydroxyestrogens are catecholestrogens, and it has been suggested that catecholestrogens increase risk of oestrogen-mediated cancers through direct genotoxic effects, rather than through stimulation of cell proliferation via binding to oestrogen receptors

the evidence is stronger for 4-hydroxyestrogens than for 2-hydroxyestrogens

a significant increase in risk of breast cancer with levels of 2-OHE1 has also been reported previously, although it was limited to hormone receptor-negative tumours

premenopausal studies on urinary EMR have suggested a potentially weak inverse relationship, associations were not significantly different compared with postmenopausal or overall combined studies

at present, there is no evidence that the EMR can predict breast cancer risk