Estrogen Induction of Hepatocellular Carcinomas in Armenian Hamsters

Coe, John E.; Ishak, Kamal G.; Ross, Mary Jane

doi:10.1002/hep.1840110408

Cited by 42 publications

(17 citation statements)

References 28 publications

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“…58 Supporting evidence is that the same mutation has been reported in hepatocellular carcinoma (HCC), 52 and estradiol, which is mainly metabolized in the liver, induces hepatocarcinogenesis. 59,60 In addition, significant associations between CYP1A1 m1 variants, an enzyme that acts in estrogen hydroxylation, and high risk of HCC in women have been reported. 61 The marker TP53-Dint was used to study primary breast cancers, showing that MSI was associated with poor prognosis of the disease.…”

Section: Discussionmentioning

confidence: 99%

Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells

Fernandez

Russo

2005

Intl Journal of Cancer

110

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An elevated incidence of breast cancer in women has been associated with prolonged exposure to high levels of estrogens. Our laboratory demonstrated that treatment of the immortalized human breast epithelial cells MCF-10F with 17b-estradiol (E 2 ), 4-hydroxyestradiol (4-OHE 2 ) or 2-hydroxyestradiol (2-OHE 2 ) induces phenotypical changes indicative of neoplastic transformation. MCF-10F cells treated with E 2 , 4-OHE 2 or 2-OHE 2 formed colonies in agar methocel and lost their ductulogenic capacity in collagen, expressing phenotypes similar to those induced by the carcinogen benzo[a]pyrene. To investigate whether the transformation phenotypes were associated with genomic changes, cells treated with E 2 , 4-OHE 2 or 2-OHE 2 at different doses were analyzed using microsatellite markers. Since microsatellite instability (MSI) and loss of heterozygosity (LOH) in chromosomes 13 and 17 have been reported in human breast carcinomas, we tested these parameters in MCF-10F cells treated with E 2 , 2-OHE 2 , or 4-OHE 2 alone or in combination with the antiestrogen ICI182780. MCF-10F cells treated with E 2 or 4-OHE 2 , either alone or in combination with ICI182780, exhibited LOH in the region 13q12.3 with the marker D13S893 located at 0.8 cM telomeric to BRCA2. Cells treated with E 2 or 4-OHE 2 at doses of 0.007 and 70 nM and 2-OHE 2 only at a higher dose (3.6 lM) showed a complete loss of 1 allele with D13S893. For chromosome 17, differences were found using the marker TP53-Dint located in exon 4 of p53. Cells treated with E 2 or 4-OHE 2 at doses of 0.007 nM and 70 nM and 2-OHE 2 only at a higher dose (3.6 lM) exhibited a 5 bp deletion in p53 exon 4. Our results show that E 2 and its catechol estrogen metabolites are mutagenic in human breast epithelial cells. ICI182780 did not prevent these mutations, indicating that the carcinogenic effect of E 2 is mainly through its reactive metabolites 4-OHE 2 and 2-OHE 2, with 4-OHE 2 and E 2 being mutagenic at lower doses than 2-OHE 2 . ' 2005 Wiley-Liss, Inc.Key words: breast cancer; estrogen; 4-OHE 2 ; 2-OHE 2 ; cell transformation Breast cancer (BC) is the most commonly occurring neoplasm and the second most frequent cause of cancer death among women in the United States. 1 There is a substantial amount of epidemiological, clinical and experimental evidence pointing to estrogens, e.g. 17b-estradiol (E 2 ), being one of the most important etiological factors for the development and progression of BC. 2-10 The risk factors include high serum or urinary estrogen concentrations, 11-13 the early onset of menstruation, and late menopause, related to prolonged exposure to estrogens. 4,14 Although the precise molecular mechanisms by which E 2 induces breast cancer have not been completely understood, the estrogen implication in breast cancer has been associated mostly with the estrogen receptor (ER) that mediates cell proliferation. 15,16 The direct role of estrogens as tumor initiators has been supported by the evidence that E 2 , catechol estrogens (CEs), and their quinone derivatives ...

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Section: Discussionmentioning

confidence: 99%

Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells

Fernandez

Russo

2005

Intl Journal of Cancer

110

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“…Endogenous hormones, androgens, and estrogen are likely to be involved in hepatic carcinogens through a receptor-mediated process. 25,26 Cryptogenic cirrhosis was another disorder in which obesity was found to be an independent risk factor. Cryptogenic cirrhosis likely represents a spectrum of diseases including nonalcoholic steatohepatitis as well as undiagnosed autoimmune liver disease and undiagnosed viral hepatitis.…”

Section: Discussionmentioning

confidence: 99%

Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?

et al. 2002

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Recently, several epidemiologic observations have suggested that obesity might be an independent risk factor for certain malignancies such as breast cancer, colon cancer, renal cell carcinoma, and esophageal adenocarcinoma. However, there are no studies examining the risk of hepatocellular carcinoma (HCC) in obesity. The aim of the present study was to determine whether obesity is an independent risk factor for HCC in patients with cirrhosis. Explanted liver specimens from a national database on patients undergoing liver transplantation were examined for HCC, and the incidence was compared among patients with varying body mass indices according to the etiology of cirrhosis. A multivariate analysis was used for controlling other potentially confounding variables such as age and sex. Among 19,271 evaluable patients, the overall incidence of HCC was 3.4% (n ‫؍‬ 659) with a slightly higher prevalence among obese patients compared with lean patients. Obesity was an independent predictor for HCC in patients with alcoholic cirrhosis (odds ratio [OR], 3.2; 95% CI, 1.5-6.6; P ‫؍‬ .002) and cryptogenic cirrhosis (OR, 11.1; 95% CI, 1.5-87.4; P ‫؍‬ .02). Obesity was not an independent predictor in patients with hepatitis C, hepatitis B, primary biliary cirrhosis, and autoimmune hepatitis. The higher risk of HCC in obese patients is confined to alcoholic liver disease and cryptogenic cirrhosis. In conclusion, more frequent surveillance for HCC may be warranted in obese patients with alcoholic and cryptogenic cirrhosis. However, as this study is based on patients with advanced cirrhosis, our findings need to be confirmed in a broader population of individuals with cirrhosis. (HEPATOLOGY 2002;36:150-155.)

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“…Animal models and human epidemiologic studies have suggested that estrogens act as tumor promoters and might induce hepatocarcinogenesis (1)(2)(3)(4). The estrogens exert the effects by binding to their receptors [estrogen receptors (ESR)].…”

Section: Introductionmentioning

confidence: 99%

Lack of Association between the Functional Polymorphisms in the Estrogen-Metabolizing Genes and Risk for Hepatocellular Carcinoma

Yuan¹,

Zhou²,

Zhai³

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Estrogens have been proposed to act as tumor promoters and induce hepatocarcinogenesis. Recently, we observed a significant association between the risk for hepatocellular carcinoma and the polymorphisms of the estrogen receptor (ESR) A (ESR1) gene, supporting the hypothesis of involvement for the estrogen-ESR axis in the estrogeninduced hepatocarcinogenesis. In this study, based on another hypothesis in which estrogen metabolites can directly cause DNA damage and affect tumor initiation, we examined whether the polymorphisms of the estrogen-metabolizing enzymes (EME), which are involved in biogenesis (CYP17, CYP19), bioavailability (CYP1A1, CYP1B1), and degradation (catechol-O-methyltransferase) of the estrogens, have any bearing on the risk for hepatocellular carcinoma. Seven functional polymorphisms in five EMEs (CYP17 MspAI site, CYP19 Trp39Arg, Ile462Val and MspI site in CYP1A1, CYP1B1 Val432Leu, and Ala72Ser and Val158Met in catechol-O-methyltransferase) were genotyped in 434 patients with hepatocellular carcinoma and 480 controls by PCR-RFLP analysis. The associations between the polymorphisms and hepatocellular carcinoma risk were evaluated while controlling for confounding factors. No significant association with the risk for hepatocellular carcinoma was observed with the seven polymorphisms in hepatitis B virus carriers and non-hepatitis B virus carriers after correction for multiple comparisons. After stratification by common confounding factors of hepatocellular carcinoma, the EME polymorphism remained no significant association with the hepatocellular carcinoma risk. Furthermore, no signs of gene-gene interactions were observed for each combination of the seven polymorphisms. Our findings suggest that the polymorphisms of EMEs may not contribute significantly to the risk for hepatocellular carcinoma. (Cancer Epidemiol Biomarkers Prev 2008;17(12):3621 -7)

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Estrogen Induction of Hepatocellular Carcinomas in Armenian Hamsters

Cited by 42 publications

References 28 publications

Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells

Estradiol and its metabolites 4‐hydroxyestradiol and 2‐hydroxyestradiol induce mutations in human breast epithelial cells

Is obesity an independent risk factor for hepatocellular carcinoma in cirrhosis?

Lack of Association between the Functional Polymorphisms in the Estrogen-Metabolizing Genes and Risk for Hepatocellular Carcinoma

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