Description
The important role played by estrogen oxidative metabolism in hormone sensitive diseases has come from studies of estrogen-dependent neoplasia of reproductive organs. With respect to breast cell malignancies, estradiol is believed to act primarily as a promotional factor, causing increased growth rates in breast cells already transformed to a cancerous state. However, estradiol is not the only active estrogen in the human body; other metabolism formed estradiol and estrone have the capacity to act as estrogens, and in some cases, as anti-estrogens. Considerable work has shown that major metabolites of estradiol are those hydroxylated at either the C-2 or the C-16α positions. There exists a complete divergence in the biological properties of the 2- and 16α-hydroxylated metabolites of estradiol. C-2 metabolites are essentially devoid of peripheral biological activity, as shown in studies on uterine weight, gonadotropin secretion, and cell proliferation. 2-Hydroxyestrogen has even been found to exert a modest antiestrogenic effect. The 16α-hydroxylated metabolite, 16α-hydroxyestrone (16-α OHE1) and estriol (E3), are estrogen agonists.
The 16-α OHE1 has several unique properties: it is capable of binding covalently to the estrogen receptor, to nuclearhistone proteins, and to DNA. Because of this covalent linkage to the receptor, 16-α OHE1 shows persistent biological responses. The formation of 16-α OHE1 is elevated in women with breast cancer, women at high risk for breast cancer, and in strains of mice with a high incidence of spontaneous mammary tumors. Estradiol 16α-hydroxylation has been shown to take place in murine and human breast epithelial cell lines, both normal and transformed, and has also been demonstrated in terminal duct lobular units (TDLU), the functional units of the breast.
In addition to the persistence in estrogenic activity described above, it was recently established that 16-α OHE1, unlike E2 or E3, possesses initiator and promoter activities in normal (non-transformed) mammary epithelial cells. In proliferation assays 16-α OHE1 had activity comparable to that observed for DMBA, unlike E2 and E3, both of which showed only minimal responses. In a mutagenic assay measuring unscheduled DNA repair, 16-α OHE1 was likewise considerably more potent than estrone (E1), E2 or E3. Measurements of anchorage independent colony formation of mammary epithelial cells grown in soft agar showed that 16-α OHE1 was far more potent than E1, E2 or E3 at increasing growth. Because the 16-hydroxylated compounds are more potent estrogens, these significant changes may have important hyperestrogenic consequences that could have a bearing upon the etiology of gynecologic cancers, especially breast cancer. Were this association proven, the ratio 2OHE1/16αOHE1 could serve as an innovative intermediate biomarker for breast cancer risk. This biomarker could be used to identify women at high risk, and provide an analytic framework for the development of new pharmaceutical and dietary intervention strategies