Biomarkers for Increased Risk of Developing Estrogen Initiated Cancer

Many types of markers are being evaluated to estimate risk of developing breast cancer. These include breast density; body mass index; expression of BRCA1 and/or BRCA2 gene; cytological changes in breast epithelial cells collected by ductal lavage; and levels of estrogens and androgens in serum, breast tissue, or nipple aspirate fluid. Some studies suggest that levels of selected estrogen metabolites, estrogen conjugates, and/or depurinating estrogen-DNA adducts in breast ductal fluid, collected either by nipple aspiration or ductal lavage, could prove to be early biomarkers of susceptibility to breast cancer. For example, in the recent study of estrogen metabolites and conjugates in breast tissue, the levels of both 4-OHE1(E2) and the combined 4-catechol estrogen-GSH, Cys, and NAcCys conjugates were significantly higher in women with breast carcinoma than in women without breast cancer (Table 1) (R1). Breast fluid is particularly attractive as a source of biomar-kers because the estrogen metabolites are more concentrated in breast fluid (C2) and it can be collected by noninvasive means.

In the future, analysis of small molecules, such as estrogen metabolites, estrogen conjugates, and depurinating estrogen-DNA adducts as biomarkers can be accomplished by using liquid chromatography/mass spectrometry. Especially promising is capillary HPLC through a short column, such as a guard column, preceding MS/MS analysis. This approach is being used now to analyze serum for a variety of small molecules, and it should also be very effective to analyze breast fluid. Estrogen metabolites with identical molecular weights, such as 2-OHE1(E2) and 4-OHE1(E2), can readily be distinguished by MS/MS (Fig. 5). Thus, if high levels of 4-OHE1(E2) turn out to

Fig. 5. MS/MS of 2-OHE2 (top) and 4-OHE2 (bottom). The 2 catechol estrogens have the same molecular weight, but are distinguishable by the primary daughter: fragment m/z = 147 for 2-OHE2 and m/z = 161 for 4-OHE2.

be a biomarker of elevated risk of breast cancer, as suggested by the data in Table 1, these estrogen metabolites can be analyzed by known MS/MS techniques. Similarly, the conjugates formed by reaction of E1(E2)-Q with GSH (Table 1) may be found to be biomarkers of susceptibility to breast cancer. The depurinating estrogen-DNA adducts, which are a direct measure of DNA damage, may ultimately be definitive biomarkers of risk of

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