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Comparative Study
. 2008 May 1;122(9):1949-57.
doi: 10.1002/ijc.23329.

The molecular etiology of breast cancer: evidence from biomarkers of risk

Nilesh W Gaikwad  1 , Li Yang, Paola Muti, Jane L Meza, Sandhya Pruthi, James N Ingle, Eleanor G Rogan, Ercole L Cavalieri
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Comparative Study

The molecular etiology of breast cancer: evidence from biomarkers of risk

Nilesh W Gaikwad et al. Int J Cancer. .
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Abstract

Estrogens can become endogenous carcinogens via formation of catechol estrogen quinones, which react with DNA to form specific depurinating estrogen-DNA adducts. The mutations resulting from these adducts can lead to cell transformation and the initiation of breast cancer. Estrogen metabolites, conjugates and depurinating DNA adducts in urine samples from 46 healthy control women, 12 high-risk women and 17 women with breast cancer were analyzed. The estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified by using ultraperformance liquid chromatography/tandem mass spectrometry. The levels of the ratios of depurinating DNA adducts to their respective estrogen metabolites and conjugates were significantly higher in high-risk women (p < 0.001) and women with breast cancer (p < 0.001) than in control subjects. The high-risk and breast cancer groups were not significantly different (p = 0.62). After adjusting for patient characteristics, these ratios were still significantly associated with health status. Thus, the depurinating estrogen-DNA adducts are possible biomarkers for early detection of breast cancer risk and response to preventive treatment.

Figures

FIGURE 1
Biosynthesis and metabolic activation of the estrogens, E1 and E2. The metabolic activation of E1 and E2 leads to 2- and 4-catechol derivatives, which further oxidize to yield the corresponding reactive quinones. The quinones 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 are conjugated with GSH, and, thus, are rendered harmless. The 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
Schematic representation of the steps carried out to purify by SPE and analyze by UPLC/MS-MS the estrogen-related compounds from urine samples. The UPLC/MS-MS chromatograms of (a) 4-OHE2, (b) 4-OHE1, (c) 4-OCH3E2, (d) 4-OCH3E1, (e) 4-OHE2-1-N7Gua, (f) 4-OHE1-1-N7Gua, (g) 4-OHE2-1-N3Ade and (h) 4-OHE1-1-N3Ade that are shown in the figure are representatives from the 40 different estrogen-related compounds seen in the urine samples.
FIGURE 3
SPE recovery of standard 40 estrogen-related compounds. The 2-ml aliquots of activated charcoal-treated human urine samples were spiked with the total (a) 250, (b) 500 and (c) 1,000 pg of 40 estrogen-related compounds before and after (control) passing over phenyl SPE cartridges. The recovery of each compound was determined by comparing the experimental values to the controls.
FIGURE 4
Depurinating estrogen-DNA adducts in the urine of healthy women, high-risk women 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 conjugates: (4-OHE1(E2)-1-N3Ade+4-OHE1(E2)-1-N7Gua4-catecholestrogens+4-catecholestrogenconjugates+2-OHE1(E2)-6-N3Ade2-catecholestrogens+2-catecholestrogenconjugates)×1000The 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 (p = 0.62). †These are 2 urine samples from the same subject, collected 11 weeks apart. Statistical calculations used 1 average value for this subject.
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