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

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 5 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. ' 2007 Wiley-Liss, Inc.Key words: breast cancer risk; depurinating estrogen-DNA adducts; estrogen biomarkers; balance in estrogen metabolism Development of noninvasive tests of breast cancer risk has been a major goal for more than 30 years. In this article we present biomarkers of risk that are related to the hypothesized first critical step in the initiation of breast cancer, namely, the reaction of catechol estrogen quinone metabolites with DNA.1 Prevention of cancer can be achieved by blocking this DNA damage, which generates the mutations leading to the initiation, promotion and progression of cancer. 2Exposure to estrogens is a known risk factor for breast cancer.3,4 The discovery that specific oxidative metabolites of estrogens, namely, catechol estrogen quinones, can react with DNA [5][6][7][8][9] led to and supports the hypothesis that these metabolites can become endogenous chemical carcinogens. Some of the mutations generated by this specific DNA damage can result in the initiation of cancer. 1,5 This paradigm suggests that specific, critical mutations generate abnormal cell proliferation leading to cancer. 1,[10][11][12][13] As illustrated in Figure 1, in the metabolism of catechol estrogens there are activating pathways 14 that lead to the formation of the estrogen quinones, estrone (estradiol) quinones [E 1 (E 2 )-Q], which can react with DNA. There are also deactivating pathways that limit formation of the quinones and/or prevent their reaction with DNA. These are methylation of catechol estrogens, 15 conjugation of the E 1 (E 2 )-Q with glutathione (GSH) 16 and reduction of the quinones to catechols 17 (Fig. 1). When E 1 (E 2 )-3,4-Q react with DNA, they form predominantly the depurinating adducts 4-hydroxyestrone(estradiol)-1-N3Ade-nine [4-OHE 1 (E 2 )-1-N3Ade] and 4-hydroxyestrone(estradiol)-1-N7Guanine [4-OHE 1 (E 2...

Inactivation of estrogen receptor by Schistosoma haematobium total antigen in bladder urothelial cells

“…Some authors have reported the presence of 4-OH-E1-1-N3Ade at 8.4 pmol/g in breast tissue from a woman with carcinoma (17), and a non-depurinating hydroxyestradiol guanosine found upon hydrolysis of DNA from breast tissues (18). Interestingly, urine levels of 4-OH-E1-1-N3Ade are low in men with prostate cancer or other urological problems (17), whereas a study involving 76 women showed high urine levels of this estrogen adduct in women at high risk of or with breast cancer, as compared to controls (19). Convert et al (20) developed an LC-MS/MS method for assessment of the reactivity of estradiol-2,3-quinone towards deoxyribonucleosides in crude reaction mixtures and proved that LC-ESI-MSn is a very powerful analytical tool for the detection of DNA-estrogen adducts generated in vivo.…”

4-Hydroxyestradiol Induces Anchorage-Independent Growth of Human Mammary Epithelial Cells via Activation of IκB Kinase: Potential Role of Reactive Oxygen Species

“…4-OHE 2 readily undergoes oxidation to estradiol-3,4-quinone that can react with DNA to form depurinating adducts (11,28). Therefore, estradiol-3,4-quinone may be an endogenous tumor initiator of breast cancer and other human malignancies (29).…”

“…Notably, the levels of 4-OHE 2 and the protein adducts of its reactive quinone metabolite were detected in the human breast tumor biopsies at significantly higher levels than those in the normal breast tissues (10). More recently, the urinary levels of depurinating DNA adducts derived from 4-OHE 2 were found to be substantially elevated in high-risk women and women with breast cancer compared with those in the control subjects (11). However, administration of 4-OHE 2 produced tumors in the kidney of Syrian hamsters (12) and uterus of CD-1 mice (13) rather than in the mammary gland.…”

Celebrating 75 years of oestradiol

“…Most believe that the pro-proliferative effects of oestrogen cause an increase in mutational errors during the process of cell replication and that an accumulation of these mutations, when unrepaired, results in breast cancer (Preston-Martin et al 1990. A more controversial concept suggests that metabolites of oestrogen are directly genotoxic (Rogan et al 2003, Cavalieri et al 2006, Yager & Davidson 2006, Saeed et al 2007, Gaikwad et al 2008, Yager 2012. Oestrogens are metabolized initially to catechol oestrogens and then oxidized to oestrogen quinones, which can bind directly to adenine and guanine.…”