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The results are compatible with the hypothesis that the increase in breast cancer risk with increasing BMI among postmenopausal women is largely the result of the associated increase in estrogens, particularly bioavailable estradiol.

Objective: Excess weight has been associated with increased risk of cancer at several organ sites. In part, this effect may be modulated through alterations in the metabolism of sex steroids and IGF-I related peptides. The objectives of the study were to examine the association of body mass index (BMI) with circulating androgens (testosterone, androstenedione and dehydroepiandrosterone sulfate (DHEAS)), estrogens (estrone and estradiol), sex hormone-binding globulin (SHBG), IGF-I and IGFbinding protein (IGFBP)-3, and the relationship between sex steroids, IGF-I and IGFBP-3. Design and methods: A cross-sectional analysis was performed using hormonal and questionnaire data of 620 healthy women (177 pre-and 443 post-menopausal). The laboratory measurements of the hormones of interest were available from two previous case-control studies on endogenous hormones and cancer risk. Results: In the pre-menopausal group, BMI was not related to androgens and IGF-I. In the post-menopausal group, estrogens, testosterone and androstenedione increased with increasing BMI. The association with IGF-I was non-linear, with the highest mean concentrations observed in women with BMI between 24 and 25. In both pre-and post-menopausal subjects, IGFBP-3 did not vary across BMI categories and SHBG decreased with increasing BMI. As for the correlations between peptide and steroid hormones, in the post-menopausal group, IGF-I was positively related to androgens, inversely correlated with SHBG, and not correlated with estrogens. In the pre-menopausal group, similar but weaker correlations between IGF-I and androgens were observed. Conclusions: These observations offer evidence that obesity may influence the levels of endogenous sex-steroid and IGF-related hormones in the circulation, especially after menopause. Circulating IGF-I, androgens and SHBG appear to be related to each other in post-menopausal women.

Among adults undergoing noncardiac surgery, MINS is common and associated with substantial mortality.

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...

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Summary The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss of function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation human liver cancer cells. Consistent with these findings, a novel, liver specific ACC inhibitor (ND-654), that mimics the effects of ACC phosphorylation, inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment.