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. 2009 Jan 6;3:1-8.
doi: 10.4137/bcbcr.s2112.

Urine biomarkers of risk in the molecular etiology of breast cancer

Nilesh W Gaikwad  1 , Li Yang, Sandhya Pruthi, James N Ingle, Nicole Sandhu, Eleanor G Rogan, Ercole L Cavalieri
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Free PMC article

Urine biomarkers of risk in the molecular etiology of breast cancer

Nilesh W Gaikwad et al. Breast Cancer (Auckl). .
Free PMC article
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Abstract

Endogenous estrogens can be bio-activated to endogenous carcinogens via formation of estrogen quinones. Estrogen-3,4-quinones react with DNA to form mutagenic depurinating estrogen-DNA adducts. The carcinogenicity of endogenous estrogens is related to unbalanced estrogen metabolism leading to excess estrogen quinones and formation of depurinating DNA adducts. The present studies were initiated to confirm that relatively high levels of depurinating estrogen-DNA adducts are present in women at high risk for breast cancer or diagnosed with the disease. These adducts may be biomarkers for early detection of breast cancer risk. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry to analyze urine samples from 40 healthy control women, 40 high-risk women and 40 women with newly diagnosed breast cancer. Estrogen metabolism was shifted from protective methoxylation and conjugation pathways in healthy control women towards activating pathways leading to formation of depurinating DNA adducts in women at high risk or with breast cancer. These results support the hypothesis that breast cancer is initiated by mutations derived from depurination of estrogen-DNA adducts. Therefore, relative levels of depurinating estrogen-DNA adducts could become biomarkers for early detection of breast cancer risk and aid in determining preventive strategies.

Keywords: balance in estrogen metabolism; breast cancer risk; depurinating estrogen-DNA adducts; urinary estrogen biomarkers.

Figures

Figure 1.
Biosynthesis and metabolic activation of the estrogens E1 and E2. One of the major metabolic pathways of E1 and E2 leads to 2- and 4-catechol derivatives, which further oxidize to yield the corresponding reactive quinones. The quinones can react with DNA to form depurinating DNA adducts. In the deactivation pathway, which operates in parallel, the catechol derivatives are methylated to form methoxy catechol estrogens; in addition, the quinones are reduced by quinone reductase, as well as being conjugated with GSH, and, are thus rendered harmless. A shift in the apparent balance between these activating and deactivating pathways towards formation of depurinating DNA adducts could lead to the initiation of breast cancer.
Figure 2.
Figure 2.
Depurinating estrogen-DNA adducts in the urine of healthy control women, women at high risk for breast cancer, and women with breast cancer. The ordinate of this bar graph corresponds to the ratio of depurinating DNA adducts divided by their respective estrogen metabolites, and thiol and methyl conjugates: [4-OHE1 (E2)-1-N3Ade+4-OHE1 (E2)-1-N7Gua4-catechol estrogens+4-catechol estrogen conjugates+2-OHE1 (E2)-6-N3Ade2-catechol estrogens+2-catechol estrogen conjugates]×1000,i.e. [No.37+38+35+36No.8+9+14+15+29 through 34+No.39+40No.6+7+12+13+16 through 28]×1000 (see Table 1 for the numbers).
Figure 3.
Mean ratios of depurinating estrogen-DNA adducts to their respective metabolites and conjugates. The mean sum of the ratios for control women was significantly lower than those for the high-risk women (p < 0.001) and women with breast cancer (p < 0.001). The mean sums of the ratios for high-risk women and women with breast cancer were not significantly different.
Figure 4.
A) Urinary median levels of 4-OHE1(E2), 4-OCH3E1(E2) and 4-OHE1(E2)-thiol conjugates, as well as 4-OHE1(E2)-1-N3Ade and 4-OHE1(E2)-1-N7Gua adducts in urine samples from 40 healthy control women, 40 high-risk women and 40 women with breast cancer. B) Urinary median levels of 2-OHE1(E2), 2-OCH3E1(E2) and 2-OHE1(E2)-thiol conjugates, as well as the 2-OHE1(E2)-6-N3Ade adducts, in urine samples from 40 healthy control women, 40 high-risk women and 40 women with breast cancer.
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References

    1. Key T, Appleby P, Barnes I, Reeves G. Endogenous sex hormones and breast cancer in postmenopausal women: reanalysis of nine prospective studies. J Natl Cancer Inst. 2002;94:606–16. - PubMed
    1. Kaaks R, Berrino F, Key T, et al. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) J Natl Cancer Inst. 2005;97:755–65. - PubMed
    1. Cavalieri EL, Li KM, Balu N, et al. Catechol ortho-quinones: the electrophilic compounds that form depurinating DNA adducts and could initiate cancer and other diseases. Carcinogenesis. 2002;23:1071–7. - PubMed
    1. Zhang L, Rothman N, Li G, et al. Aberrations in chromosomes associated with lymphoma and therapy-related leukemia in benzene-exposed workers. Environ Mol Mutagen. 2007;48:467–74. - PubMed
    1. Smith MT, Jones RM, Smith AH. Benzene exposure and risk of non-Hodgkin lymphoma. Cancer Epidemiol Biomarkers Prev. 2007;16:385–91. - PubMed

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