Urine Biomarkers of Risk in the Molecular Etiology of Breast Cancer

Gaikwad, Nilesh W.; Yang, Liangcheng; Pruthi, Sandhya; Ingle, James N.; Sandhu, Nicole P.; Rogan, Eleanor G.; Cavalieri, Ercole L.

doi:10.4137/bcbcr.s2112

Cited by 53 publications

(120 citation statements)

References 27 publications

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“…Release of the depurinating adducts leaves apurinic sites in the DNA, which, in turn, induce mutations. It is thought that critical mutations generated by specific DNA damage can result in abnormal cell proliferation leading to cancer (Chakravarti et al 2001, Fernandez et al 2006, Mailander et al 2006, Zhao et al 2006, 2009a. All of these results support the hypothesis that estrogens could initiate NHL through the formation of depurinating DNA adducts.…”

Section: Introductionsupporting

confidence: 77%

“…Several factors can unbalance estrogen homeostasis, which is the equilibrium between estrogen activating and deactivating pathways that minimizes oxidation of catechol estrogens to quinones, and their subsequent reaction with DNA ( Figure 2) . A similar disruption in estrogen homeostasis has also been observed in men with prostate cancer (Yang et al 2009) and women with breast cancer (Gaikwad et al , 2009a, as well as several animal models of estrogen carcinogenesis , 2002a, Devanesan et al 2001). …”

Section: Discussionmentioning

confidence: 79%

“…the levels of depurinating estrogen-DNA adducts are high and/or the levels of estrogen metabolites and conjugates are low. Although the elevated adduct formation is tissue specific, we have demonstrated empirically in earlier studies of breast and prostate cancer patients that these adduct biomarkers are excreted in the urine at higher concentrations , 2009a, Yang et al 2009). …”

Section: Discussionmentioning

confidence: 99%

“…The predominant depurinating estrogen-DNA adducts, 4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua (Cavalieri et al 1997, Li et al 2004, are shed from cells into the bloodstream and, eventually, are excreted in urine, where they can be analysed, along with estrogen metabolites and conjugates (Gaikwad et al , 2009a. Release of the depurinating adducts leaves apurinic sites in the DNA, which, in turn, induce mutations.…”

Section: Introductionmentioning

confidence: 99%

“…Considering the resemblance of bioactivation of endogenous estrogens and benzene, their effects on lymphoid tissue in animals (Li 1996, Forsberg 1984, association of polymorphisms in estrogen biosynthesis and metabolism with NHL in humans (Skibola et al 2005a(Skibola et al , b, 2007(Skibola et al , 2008, our recent success in establishing the chain of reactions that lead to estrogen carcinogenesis (Gaikwad et al , 2009a) and the discovery that the level of estrogen-DNA adducts in urine correlates with risk of developing breast cancer (Gaikwad et al , 2009a, we were interested to test the hypothesis that depurinating DNA adducts may be involved in the aetiology of NHL. The results presented in this article suggest that the levels of estrogen metabolites, conjugates and depurinating DNA adducts differ significantly between healthy men and men with NHL.…”

Section: Introductionmentioning

confidence: 99%

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Urinary biomarkers suggest that estrogen-DNA adducts may play a role in the aetiology of non-Hodgkin lymphoma

Gaikwad¹,

Yang²,

Weisenburger³

et al. 2009

Biomarkers

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A variety of evidence suggests that estrogens may induce non-Hodgkin lymphoma (NHL). The reaction of catechol estrogen quinones with DNA to form depurinating estrogen-DNA adducts is hypothesized to initiate this process. These adducts are released from DNA, shed from cells into the bloodstream and excreted in urine. The aim of this study was to determine whether or not the depurinating estrogen-DNA adducts might be involved in the aetiology of human NHL. Estrogen metabolites, conjugates and depurinating DNA adducts were identified and quantified in spot urine samples from 15 men with NHL and 30 healthy control men by using ultraperformance liquid chromatography/tandem mass spectrometry. The levels of estrogen-DNA adducts were significantly higher in the men with NHL than in the healthy control men. Thus, formation of estrogen-DNA adducts may play a critical role in the aetiology of NHL, and these adducts could be potential biomarkers of NHL risk.

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Section: Introductionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Urinary biomarkers suggest that estrogen-DNA adducts may play a role in the aetiology of non-Hodgkin lymphoma

Gaikwad¹,

Yang²,

Weisenburger³

et al. 2009

Biomarkers

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Human Biomonitoring of DNA Adducts by Ion Trap Multistage Mass Spectrometry

Guo

Turesky

2016

CP Nucleic Acid Chemistry

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Humans are continuously exposed to hazardous chemicals in the environment. These chemicals or their electrophilic metabolites can form adducts with genomic DNA, which can lead to mutations and the initiation of cancer. The identification of DNA adducts is required for understanding exposure and the etiological role of a genotoxic chemical in cancer risk. The analytical chemist is confronted with a great challenge because the levels of DNA adducts generally occur at less than one adduct per 107 nucleotides, and the amount of tissue available for measurement is limited. Ion trap mass spectrometry has emerged as an important technique to screen for DNA adducts because of the high level sensitivity and selectivity, particularly, when employing multi-stage scanning (MSn). The product ion spectra provide rich structural information and corroborate the adduct identities even at trace levels in human tissues. Ion trap technology represents a significant advance in measuring DNA adducts in humans.

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Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: The defining link to natural estrogens

Saeed

Rogan²,

Cavalieri³

2008

Intl Journal of Cancer

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Diethylstilbestrol (DES) is a human carcinogen, based on sufficient epidemiological evidence. DES is mainly metabolized to its catechol, 3 0 -hydroxyDES (3 0 -OH-DES), which can further oxidize to DES-3 0 ,4 0 -quinone (DES-3 0 ,4 0 -Q). Similarly to estradiol-3,4-quinone, the reaction of DES-3 0 ,4 0 -Q with DNA would form the depurinating 3 0 -OH-DES-6 0 -N3Ade and 3 0 -OH-DES-6 0 -N7Gua adducts. To prove this hypothesis, synthesis of DES-3 0 ,4 0 -Q by oxidation of 3 0 -OH-DES with Ag 2 O was tried; this failed due to instantaneous formation of a spiro-quinone. Oxidation of 3 0 -OH-DES by lactoperoxidase or tyrosinase in the presence of DNA led to the formation of 3 0 -OH-DES-6 0 -N3Ade and 3 0 -OH-DES-6 0 -N7Gua adducts. These adducts were tentatively identified by LC-MS/MS as 3 0 -OH-DIES with DNA did not produce any depurinating adducts, due to the dienic chain being perpendicular to the phenyl planes, which impedes the intercalation of DIES into the DNA. Enzymic oxidation of 3 0 -OH-DES suggests that the catechol of DES intercalates into DNA and is then oxidized to its quinone to yield N3Ade and N7Gua adducts. These results suggest that the common denominator of tumor initiation by the synthetic estrogen DES and the natural estrogen estradiol is formation of their catechol quinones, which react with DNA to afford the depurinating N3Ade and N7Gua adducts. ' 2008 Wiley-Liss, Inc.Key words: DES catechol quinone; depurinating DES-DNA adducts; metabolic activation of DES Diethylstilbestrol (DES), a potent synthetic estrogen, was obtained in 1938 and thereafter used to prevent spontaneous abortions and premature deliveries.1 In 1971 an association was found between prenatal exposure to DES and clear cell adenocarcinoma of the vagina and cervix in young women.2 Evidence for a causal relationship between transplacental exposure to DES and clear cell adenocarcinoma is conclusive.3-5 Furthermore, it was later reported that women who took DES during pregnancy had a higher incidence of breast cancer.6,7 More recently, it was found that women exposed to DES prenatally also have a higher incidence of breast cancer after age 40. 8,9 The natural estrogens estradiol (E 2 ) and estrone (E 1 ) are metabolically oxidized to their respective catechols, and the catechols are subsequently oxidized to their quinones, in particular the E 1 (E 2 )-3,4-quinones (Q). We have proposed and demonstrated that reaction of the E 1 (E 2 )-3,4-Q with DNA is the first critical step in the initiation of cancer.10-13 The depurinating adducts 4-OHE 1 (E 2 )-1-N3Ade and 4-OHE 1 (E 2 )-1-N7Gua, as well as the resulting apurinic sites in the DNA, are formed in this reaction. These apurinic sites generate mutations that we think can lead to cancer initiation. 13-15The same mechanism of metabolic activation and reaction with DNA has been demonstrated for the synthetic estrogen hexestrol (HES). 16,17 The catechol quinone of HES has chemical and biochemical properties similar to those of E 1 (E 2 )-3,4-Q; namely, it forms analogous depurinating N3Ade...

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Urine Biomarkers of Risk in the Molecular Etiology of Breast Cancer

Cited by 53 publications

References 27 publications

Urinary biomarkers suggest that estrogen-DNA adducts may play a role in the aetiology of non-Hodgkin lymphoma

Urinary biomarkers suggest that estrogen-DNA adducts may play a role in the aetiology of non-Hodgkin lymphoma

Human Biomonitoring of DNA Adducts by Ion Trap Multistage Mass Spectrometry

Mechanism of metabolic activation and DNA adduct formation by the human carcinogen diethylstilbestrol: The defining link to natural estrogens

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