Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The modifying effects of dietary feeding of atrazine, which is one of the endocrine disrupting chemicals (EDCs), on 7,12-dimethylbenz(a)anthracene (DMBA)-induced ovarian carcinogenesis were investigated in female Sprague-Dawley rats. We also assessed the effect of atrazine on proliferating cell nuclear antigen (PCNA)-index and the expression of estrogen receptor (ER)-alpha and -beta and androgen receptor (AR) in induced neoplasms. Rats were given a single injection of DMBA (0.01 ml of 0.5% DMBA suspended in olive oil) into their left ovary to induce ovarian neoplasms. They also received the experimental diet containing 5, 50 or 500 ppm atrazine for 50 weeks, starting one week after the dosing of DMBA. The diets used were free of soy products. DMBA exposure produced left ovarian adenocarcinoma with an incidence of 45% at the end of the study (week 51). Dietary administration atrazine reduced the incidence of ovarian adenocarcinoma: 22, 28, and 26% incidences in rats fed 5, 50, and 500 ppm atrazine containing diets after DMBA exposure, respectively, without statistical significance among the groups. The PCNA-index in adenocarcinomas was greater than that of surface ovarian epithelium. ER-alpha, beta and AR were expressed in a variable percentage of moderately and poorly differentiated adenocarcinoma cell nuclei, but their reactivity was extremely weak or negative in well differentiated adenocarcinoma cells. These results might suggest dietary feeding of a EDC atrazine did not affect DMBA-induced rat ovarian carcinogenesis.
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PMID:Lack of modifying effects of an estrogenic compound atrazine on 7,12-dimethylbenz(a)anthracene-induced ovarian carcinogenesis in rats. 1518 28

The ability of celecoxib and alpha-difluoromethylornithine (DFMO) to modulate the DNA hypomethylation and the hypermethylation of the estrogen receptor (ER)-alpha gene in colon tumors was evaluated as potential biomarkers for chemoprevention. Colon tumors were induced in rats by azoxymethane. Celecoxib (500 mg/kg), DFMO (100, 1000 and 3000 mg/kg) or celecoxib + 1000 mg/kg DFMO were administered in the diet for 7 or 28 days prior to death at week 37. Relative to the normal colon mucosa, colon tumors contained global hypomethylated DNA but simultaneous hypermethylation of the promoter plus exon-1 region of the ER-alpha gene. Limited treatment with celecoxib (500 p.p.m. in diet) or DFMO (1000 or 3000 p.p.m. in diet) reversed the DNA hypomethylation. Administering 1000 and 3000 p.p.m. DFMO for 7-days decreased the number of methylated CpG sites in the ER-alpha gene from 5.00 +/- 0.95 to 3.83 +/- 0.75 and 1.75 +/- 0.49 these levels were further reduced to 0.50 +/- 0.26 following administration of 1000 mg/kg for 28 days. Celecoxib administered for 7 and 28 days reduced the number of methylated sites to 4.25 +/- 0.48 and 1.5 +/- 0.50. The combination containing celecoxib and DFMO reduced the number of methylated sites to 0.20 +/- 0.20 at both 7 and 28 days. In parallel with the hypermethylation of the ER-alpha gene, the mRNA expression of the gene was decreased in colon tumors and was increased by celecoxib, DFMO or the combination. Celecoxib and DFMO reversed DNA hypomethylation and the hypermethylation of the ER-alpha gene in colon tumors supporting the hypothesis that modulation of methylation is a biomarker of chemoprevention.
Carcinogenesis 2004 Oct
PMID:Modulation by celecoxib and difluoromethylornithine of the methylation of DNA and the estrogen receptor-alpha gene in rat colon tumors. 1520 57

Breast carcinoma is the most common form of neoplasia in women of the Western world, and the mortality from this disease in women is second only to that of lung cancer, with a means incidence of 10%. Although, several studies have indicated that the development of this fairly heterogeneous disease depends on a great many environmental, socio-economic, hormonal and genetic factors, the pathogenesis of breast cancer remains poorly understood. ER-alpha (estrogen-receptor alpha) and its ligand (17beta-estradiol) play a crucial role in normal breast development and have also been linked to mammary carcinogenesis and clinical outcome in breast cancer patients. The estrogen signaling regulates the growth of some breast tumors, and antiestrogen therapies can effectively block this growth signaling resulting in tumor suppression. However, most tumors eventually develop antiestrogen resistance, and antiestrogen are mostly ineffective in patience with advanced disease. Although several studies have been proposed that epigenetic events could be involved in ER-alpha silencing the mechanisms regulating ER-alpha transcription are poorly understood. Our studies suggested that pRb2/p130-complexes bind to the ER-alpha promoter and could be involved in the transcriptional regulation of the ER-alpha gene by altering chromatin structure and DNA methylation pattern.
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PMID:The regulation of ER-alpha transcription by pRb2/p130 in breast cancer. 1592 24

The breast and ovarian cancer susceptibility gene-1 (BRCA1) located on chromosome 17q21 encodes a tumor suppressor gene that functions, in part, as a caretaker gene in preserving chromosomal stability. The observation that most BRCA1 mutant breast cancers are hormone receptor negative has led some to question whether hormonal factors contribute to the etiology of BRCA1-mutant breast cancers. Nevertheless, the caretaker function of BRCA1 is a generic one and does not explain why BRCA1 mutations confer a specific risk for tumor types that are hormone-responsive or that hormonal factors contribute to the etiology, including those of the breast, uterus, cervix, and prostate. An accumulating body of research indicates that in addition to its well-established roles in regulation of the DNA damage response, the BRCA1 protein interacts with steroid hormone receptors (estrogen receptor (ER-alpha) and androgen receptor (AR)) and regulates their activity, inhibiting ER-alpha activity and stimulating AR activity. The ability of BRCA1 to regulate steroid hormone action is consistent with clinical-epidemiological research suggesting that: (i) hormonal factors contribute to breast cancer risk in BRCA1 mutation carriers; and (ii) the spectrum of risk-modifying effects of hormonal factors in BRCA1 carriers is not identical to that observed in the general population. These data suggest a model for BRCA1 carcinogenesis in which genomic instability leads to the initiation of cancerous cell clones, while loss of normal restraint on hormonal stimulation of mammary epithelial cell proliferation allows amplification of these pre-existing clones. Further research will be required to substantiate this hypothesis.
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PMID:BRCA1 in hormonal carcinogenesis: basic and clinical research. 1617 91

Epidemiologic studies have implicated estrogenic exposure as well as human papilloma virus (HPV) infection in cervical carcinogenesis, and some studies have suggested that estrogen and HPV may play synergistic roles in cervical tumorigenesis. In this study, we report a novel finding that approximately 35% of cervical carcinomas tested (n = 19) express aromatase, the enzyme responsible for converting androgen to estrogen, the rate-limiting and final step in estrogen biosynthesis. On the other hand, no aromatase expression was detected in precancerous (n = 42) or normal cervical (n = 17) tissue samples. Increased aromatase was associated with increases in estrogen receptors (ER-alpha and ER-beta) and a decrease in progesterone receptor levels, suggesting that in situ estrogen signaling via ER may be involved in tumor growth. Stable overexpression of aromatase in HPV+ cervical cancer cells resulted in increased cellular proliferation, anchorage-independent growth, and ER expression and activity. In contrast, little change in ER was observed in HPV- cells. Steroid hormone receptor expression observed in vitro paralleled that seen in cervical carcinomas expressing aromatase. Aromatase overexpression also induced the expression of cyclin D1, proliferating cell nuclear antigen, and the HPV oncogenes, E6 and E7. Furthermore, the data underscores the importance of steroid receptor (estrogen and progesterone receptors) regulation in cervical carcinogenesis. To our knowledge, this is the first report demonstrating the induction of aromatase expression in cervical carcinomas, and opens the possibility that aromatase inhibitors may be potential therapeutic agents in cervical carcinomas expressing aromatase.
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PMID:Induction of aromatase expression in cervical carcinomas: effects of endogenous estrogen on cervical cancer cell proliferation. 1632 67

Epidemiologic data have suggested that green tea may prevent breast cancer. Studies in our laboratory have provided evidence that green tea extract inhibits breast cancer growth by a direct anti-proliferative effect on the tumor cells, as well as by indirect suppressive effects on the tumor-associated endothelial cells. In this study, we asked whether concurrent administration of green tea may add to the anti-tumor effects of standard breast cancer therapy. We observed that green tea increased the inhibitory effect of tamoxifen on the proliferation of the ER (estrogen receptor)-positive MCF-7, ZR75, T47D human breast cancer cells in vitro. This combination regimen was also more potent than either agent alone at increasing cell apoptosis. In animal experiments, mice treated with both green tea and tamoxifen had the smallest MCF-7 xenograft tumor size, and the highest levels of apoptosis in tumor tissue, as compared with either agent administered alone. Moreover, the suppression of angiogenesis in vivo correlated with larger areas of necrosis and lower tumor blood vessel density in treated xenografts. Green tea decreased levels of ER-alpha in tumors both in vitro and in vivo. We also observed that green tea blocked ER-dependent transcription, as well as estradiol-induced phosphorylation and nuclear localization of mitogen-activated protein kinase. To our knowledge, this study is the first to show the interaction of green tea with the ER pathway, as well as provide mechanistic evidence that the combination of green tea and tamoxifen is more potent than either agent alone in suppressing breast cancer growth. These results may lead to future improvements in breast cancer treatment and prevention.
Carcinogenesis 2006 Dec
PMID:The combination of green tea and tamoxifen is effective against breast cancer. 1678 49

An evaluation of the effects of a traditional Chinese herbal medicine, Hochu-ekki-to (Bu-zong-yi-qi-tang) on endometrial carcinogenesis was performed in experiments with female mice. In the short-term experiment, dietary exposure of Hochu-ekki-to (0.2% for 2 weeks) decreased the estradiol-17beta (E2)-stimulated expression levels of c-jun (P<0.001), tumor necrosis factor (TNF)-alpha (P<0.005), estrogen receptors (ER)-alpha (P<0.001) and ER-beta (P<0.005), as determined by reverse transcription-polymerase chain reaction and a Southern blot analysis in the uteri of the ovarectomized mice. In the long-term experiment, the mice were given N-methyl-N-nitrosourea (MNU) solution (1 mg/100 g body weight) and normal saline (as controls) into their left and right uterine corpora, respectively, and then were divided into four groups. Group 1 (25 mice) was given a diet with Hochu-ekki-to and 5 ppm E2. Group 2 (25 mice) was given a diet with E2 alone. Group 3 (25 mice) was given a diet with Hochu-ekki-to alone. Group 4 (25 mice) was kept on the basal diet alone and treated as a control. The incidence of uterine endometrial cancer in the group with Hochu-ekki-to treatment was substantially lower than of the control group. The inhibitory effect of Hochu-ekki-to on endometrial carcinogenesis is thus suggested to decrease the expressions of c-jun, TNF-alpha, ER-alpha and -beta.
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PMID:Inhibitory effects of Hochu-ekki-to on endometrial carcinogenesis induced by N-methyl-N-nitrosourea and 17beta-estradiol in mice. 1708 59

The objectives were to study the expression of receptor-binding cancer antigen expressed on SiSo cells (RCAS1) and estrogen receptor (ER) subtypes in the normal, hyperplastic, and carcinomatous endometrium and to explore their possible role in carcinogenesis and progression of endometrial carcinoma. Immunohistochemistry and semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR) were applied to detect protein and messenger RNA expression of RCAS1, ER-alpha, and ER-beta in normal, hyperplastic, and carcinomatous endometrium. Western blotting was also used to detect the RCAS1 protein expression. Immunohistochemistry showed that the high expressions of RCAS1 protein were 0% (0/20), 9.1% (2/22), 40% (8/20), and 68.0% (34/50) in normal, simple, and complex hyperplasia, atypical hyperplasia, and endometrial carcinoma, respectively. There was a significant difference between each group (P < 0.05). The high-level expression of RCAS1 was detected more frequently in endometrial cancer with deep myometrial invasion, vascular invasion, and positive ER-alpha (P < 0.05). Two staining patterns of RCAS1 were observed. All normal, simple, and complex hyperplastic endometrium showed P pattern, while all malignant endometrium were of the D pattern. In atypical endometrium, 25% (5/20) cases showed D pattern. The Western blotting and RT-PCR results correlated with the immunohistochemistry results. The expression and distribution of RCAS1 may be involved in the malignant transformation of endometrium, and RCAS1 coexpression with ER-alpha may be associated with development and metastasis of endometrial carcinoma.
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PMID:Expression of receptor-binding cancer antigen expressed on SiSo cells and estrogen receptor subtypes in the normal, hyperplastic, and carcinomatous endometrium. 1746 50

Breast carcinoma is one of the most common malignancies in women, and its carcinogenesis is still unknown. The role of microsatellite instability (MSI) in breast carcinogenesis has been inconsistent in the literature. Here we studied the expression of 2 mismatch repair genes, hMLH1 and hMSH2, in 211 cases of intraductal (DCIS; 90 cases) and invasive ductal carcinoma (121 cases) of the breast by immunohistochemical analysis; and evaluated its relationship with cytokeratin (CK) subtypes, along with expression of ER-alpha (138 cases positive, 73 cases negative); PR (118 cases positive, 93 cases negative), and HER-2/neu (47 cases positive, 164 cases negative); and clinical features such as patient age (157 cases>50 years, 54 cases<50 years), tumor size (31 cases of IDC>2 cm, 90 cases of IDC<2 cm), tumor grade (87 cases high nuclear grade, 124 case non-high grade), and lymph node metastasis (38 cases of IDC positive, 74 cases of IDC negative, 9 cases of IDC with no available data on lymph node status). For CK subtypes, 167 cases were classified as luminal subtype (expressing CK8 and/or CK18, negative for CK5/6, CK14, and CK17) and 44 cases were classified as nonluminal (most of them belonged to basal/stem subtype, expressing CK5/6, and/or CK14, and/or CK17). No typical or atypical medullary carcinoma was included in this study. Our results showed that no loss of nuclear expression of either hMLH1 or hMSH2 was identified in any of the 211 cases of DCIS or IDC regardless of the various pathological and clinical factors, suggesting that hMLH1 or hMSH2 may not play an essential role in the majority of cases of the breast carcinoma.
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PMID:Mismatch repair genes hMLH1 and hMSH2 may not play an essential role in breast carcinogenesis. 1765 29

The designation lobular neoplasia (LN) of the breast includes atypical lobular hyperplasia and lobular carcinoma in situ. Estrogen receptors (ER) play a significant role in breast carcinogenesis. In the present study, ER-alpha and ER-beta status are evaluated in 30 breast tissue specimens from patients whose main lesion was LN. A standard immunohistochemical procedure, using monoclonal antibodies for ER-alpha and ER-beta, was applied to the lesion and the adjacent normal breast tissues, the latter serving as control. In all cases, both receptors were expressed in LN as well as in normal breast ducts and lobules. Concerning ER-alpha, the Allred score and the percentage of ER-alpha-positive cells were significantly higher in LN than in the adjacent normal breast tissue. On the contrary, regarding ER-beta, the Allred score and the percentage of ER-beta-positive cells were significantly lower in LN compared with normal adjacent breast tissue. Greater increase in the percentage of ER-alpha-positive cells was associated with a smaller reduction in the percentage of ER-beta-positive cells and vice versa (Spearman's rho = -0.5044, p = 0.001). In conclusion, upregulation of ER-alpha and downregulation of ER-beta may represent two discrete molecular events in LN pathogenesis. Of notice, a mutually limiting interaction may exist between the two events.
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PMID:Immunohistochemical expression of estrogen receptors alpha and beta in lobular neoplasia. 1792 41


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