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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The involvement of rotenone in rat mammary carcinogenesis has been suggested to occur through estrogenic effects. This hypothesis was tested by determining the extent of rotenone inhibition of 17 beta-estradiol binding to the estrogen receptor and of the 17 beta-estradiol-induced uterotrophic response in ovariectomized Sprague-Dawley rats. Estradiol binding to the uterine estrogen receptor in the presence of rotenone was determined by charcoal assay and Scatchard analysis. Additionally, 17 beta-estradiol-receptor interactions were assessed on sucrose density gradients. No inhibition of binding was observed in either assay with ratios of rotenone/17 beta-estradiol in excess of 10,000. Finally, an in vivo approach was used to extend the in vitro data. Silastic capsules containing rotenone or 17 beta-estradiol were implanted in various combinations into eight groups of ovariectomized Sprague-Dawley rats (four rats/group). After five days, uteri were removed and weighed. An analysis of variance revealed that rotenone neither interfered with 17 beta-estradiol-induced uterine weight gain nor displayed any uterotrophic properties by itself. Results from these three procedures demonstrate that rotenone does not act as an estrogen or as an estrogen antagonist. Additionally, there were no other effects attributable to rotenone.
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PMID:Failure of rotenone to interfere with 17 beta-estradiol action in the rat uterus. 49 75

Treatment of MCF-7 cells with 1.0 microM 3-methylcholanthrene (MC) caused a decrease in cell proliferation and [3H]thymidine uptake whereas no effects were observed at a lower (0.1 microM) concentration. Co-treatment of the cells with 1 nM 17 beta-estradiol plus 0.1 or 1.0 mu MC resulted in a significant inhibition of 17 beta-estradiol-induced growth and [3H]thymidine uptake. MC also inhibited the 17 beta-estradiol-induced secretion of the 52 kDa protein (procathepsin D) in MCF-7 cells and caused a concentration-dependent decrease in the nuclear estrogen receptor (ER) as determined by either velocity sedimentation analysis or immunoquantitation with human ER antibodies. The effects of several different polynuclear aromatic hydrocarbon (PAH) congeners on the nuclear ER in MCF-7 cells were also determined. Only those congeners which bound to the aryl hydrocarbon (Ah) receptor, namely benzo[a]pyrene, benz[a]anthracene, 7,12-dimethylbenz[a]anthracene and MC, caused a decrease in nuclear ER levels. In contrast, benzo[ghi]perylene, a congener which did not bind to the Ah receptor did not affect nuclear ER levels in MCF-7 cells. Moreover, with some congeners the decrease in nuclear ER levels could be observed without any significant induction of ethoxyresorufin O-deethylase activity, a P4501A1-dependent monooxygenase. These data suggest that the Ah receptor liganded with MC and related PAHs induced a broad spectrum of antiestrogenic responses in MCF-7 cells and complements the results of previous studies which report the antiestrogenic effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin and other halogenated aromatics which are also Ah receptor agonists.
Carcinogenesis 1992 Dec
PMID:Polynuclear aromatic hydrocarbon carcinogens as antiestrogens in MCF-7 human breast cancer cells: role of the Ah receptor. 133 74

Rat mammary carcinomas were induced by directly inserting activated neu or ras genes into in situ rat mammary ductal cells using replication-defective retroviral vectors. neu was over 200 times more potent than ras in inducing rat mammary carcinomas. Ovariectomy 2 days postinfection dramatically reduced the occurrence of carcinomas induced by neu and extended their latency. In general, early ovariectomy had much less effect on the occurrence of carcinomas induced by ras and had no significant effect on their latency. Carcinomas induced by neu in ovariectomized rats had down-regulated estrogen receptor and progesterone receptor, while those induced by ras had only down-regulated progesterone receptor. Fully progressed mammary carcinomas in intact rats induced by both neu and ras had a similar response to ovariectomy, with an approximate regression rate of 60%. These data suggest that the activation of ras, but not neu, can replace at least some functions performed by ovarian hormones in the early phases of mammary carcinogenesis. These data also suggest a role for antiestrogen drug therapy in the prevention of neu-associated breast cancer.
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PMID:Difference in the response of neu and ras oncogene-induced rat mammary carcinomas to early and late ovariectomy. 135 10

Inbred rats of the DA/Han and BDII/Han strains have been proposed as suitable model systems for studying hormonal carcinogenesis, because they die mainly from hormone-dependent endometrial adenocarcinoma. Here we characterize the RUCA-I cell line derived from an endometrial adenocarcinoma of an inbred DA/Han rat and the RUCA-II cell line derived from an endometrial adenocarcinoma of an inbred BDII/Han rat. The RUCA-I cell line, if transplanted to the neck of female DA/Han rats, gives rise to endometrial adenocarcinomas at the ectopic site. The morphology of these ectopically grown tumors is predominantly of the moderately differentiated sub-class. In contrast, ectopic tumor growth of the RUCA-II cell line can be observed only if cells are transplanted to athymic nude mice. Biochemically, both cell lines are characterized by the stable expression of estrogen receptors. However, no statistically significant mitotic response of RUCA-I and RUCA-II cells to estradiol was measurable, and no induction of expression of the progesterone receptor by estradiol was detectable, although estradiol transformed the estrogen receptor into its stable DNA-binding state. In contrast, the rate of proliferation of RUCA-I but not of RUCA-II cells was reduced in the presence of 10(-6) M tamoxifen. From these results we conclude that (i) both cell lines, RUCA-I and RUCA-II, represent a new and promising endometrial tumor model; (ii) the mechanism of the hormone-dependent growth regulation of RUCA-I and RUCA-II cells is obviously impaired; (iii) the RUCA-I cell line appears to be a suitable model system for the study of molecular aspects of estrogen- and tamoxifen-dependent gene expression.
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PMID:Functions of estrogens and anti-estrogens in the rat endometrial adenocarcinoma cell lines RUCA-I and RUCA-II. 145 35

Trans-tamoxifen (TAM) has been used successfully in therapy for estrogen-dependent human breast tumors and prevention of their recurrence. The mechanism of this prevention was thought to be due to the interference of TAM with estrogen promotion. TAM has a wider anticarcinogenic action that is similar to other chemopreventive agents in that it suppresses tumor promotion in 2-stage carcinogenesis by interfering with the action of protein kinase C. We report that TAM (5 microM) totally inhibits hydrogen peroxide (H2O2) formation by 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-treated human neutrophils. Interestingly, beta-estradiol (10 microM) also slightly inhibits the oxidative burst of neutrophils. Pretreatment of neutrophils with varying amounts of TAM and beta-estradiol caused additive inhibition of H2O2 formation by the 2 agents. 4-Hydroxy-tamoxifen, a metabolite with the highest affinity for the estrogen receptor, was only as inhibitory as beta-estradiol. Other derivatives (cis-, N-desmethyl-, and N-desdimethyl-tamoxifen) with low biological activities had a smaller effect on H2O2 formation. TPA-treated neutrophils were shown to contain 5-hydroxymethyl uracil (HMU). TAM prevented the TPA-induced formation of HMU in other cells. Like TPA, dietary fat, which is a risk factor for breast cancer, induces formation of HMU in the DNA of human white blood cells. TAM may suppress the dietary fat-induced HMU in the same manner at it does in TPA-induced neutrophils.
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PMID:Tamoxifen suppresses tumor promoter-induced hydrogen peroxide formation by human neutrophils. 151 53

17 alpha-Ethinylestradiol (EE2)-mediated promotion of diethylnitrosamine (DEN)-initiated liver tumors was evaluated in distinct hepatocyte subpopulations. Our initiation-promotion regime consisted of a single dose of DEN (200 mg/kg) to ovariectomized rats, followed by chronic exposure to EE2 (90 micrograms/kg/day for 30 weeks). We observed significant increases in liver and uterine organ wts which were associated with liver tumor formation. Isolated hepatocytes were separated by elutriation into seven subpopulations. The early eluting subpopulations consisted of a greater proportion of diploid cells and they exhibited a preferential uptake of acridine orange, which is characteristic of periportal cells. With the increasing order of elutriated fractions, hepatocyte subpopulations of tetraploid and octaploid cells were obtained. Elutriation revealed that EE2 promotion enhanced nuclear estrogen receptor levels (3-fold) and gamma-glutamyltranspeptidase activity (5-fold) to a greater extent in the early eluting diploid subpopulations (1 and 2), even though total estrogen receptor (ER) levels were higher in the later eluting subpopulations. The stimulatory effect of EE2 on ER levels was associated with an increased ER occupancy in all subpopulations, although the effect was greatest in the later eluting fractions. Chronic EE2 exposure induced the emergence of new hepatocyte populations within fractions 6 and 7. Enhanced cell growth was observed in the DEN/EE2-derived hepatocytes by flow cytometric measurements of DNA synthesis. The new populations of altered cells expressed high levels of epidermal growth factor receptor (EGFR), with 90% of the cells positive for EGFR-antibody. In summary, our data demonstrate that many effects of EE2 on hepatocyte pathways involved in growth control occur in nearly all populations of cells, derived by elutriation although some effects such as the emergence of an EGFR-enriched population of hepatocytes are localized in specific populations.
Carcinogenesis 1991 Mar
PMID:Estrogen receptor, epidermal growth factor receptor and cellular ploidy in elutriated subpopulations of hepatocytes during liver tumor promotion by 17 alpha-ethinylestradiol in rats. 167 26

Zeranol (alpha-zearalanol) is a beta-resorcylic acid lactone (RAL) that has estrogen activity. It is synthesized by molds and is difficult to avoid in human food products. We tested the ability of this mycoestrogen to damage the liver of the Armenian hamster, a rodent that is especially sensitive to hepatotoxic effects of exogenous estrogens. Zeranol induced acute hepatotoxicity and, subsequently, hepatic carcinogenesis; both effects were blocked by tamoxifen, suggesting estrogen receptor mediation. Because zeranol is acting alone as a primary initiator of hepatic neoplasms, this model provides an unusual opportunity to study the pathogenesis of estrogen-initiated tumorigenesis.
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PMID:Tamoxifen prevents induction of hepatic neoplasia by zeranol, an estrogenic food contaminant. 173 91

The N-methyl-N-nitrosourea (NMU) model of hormone-responsive rat mammary carcinogenesis was used to address the hypothesis that melatonin (Mel), the principle hormone of the pineal gland, inhibits tumorigenesis by acting as an anti-promoting rather than an anti-initiating agent. Daily late-afternoon injections of Mel (500 micrograms/day), restricted to the initiation phase of NMU mammary tumorigenesis, were ineffective in altering tumor growth over a 20-week period. When Mel treatment was delayed for 4 weeks after NMU and then continued through the remainder of the promotion phase, only tumor number was significantly lower than in controls. However, when Mel injections encompassed the entire promotion phase, both tumor incidence and number were significantly lower than in the controls. Although elimination of the endogenous Mel signal via pinealectomy promoted tumor growth, the effect was not statistically significant. Serum levels of estradiol and tumor estrogen receptor content were unaltered by either Mel or pinealectomy. While Mel treatment failed to affect circulating prolactin levels, pinealectomy caused a two-fold increase in serum prolactin. The estradiol-stimulated recrudescence of tumors following ovariectomy was completely blocked by either 20, 100 or 500 micrograms Mel/day or tamoxifen (20 micrograms/day). Thus, Mel appears to be an anti-promoting hormone that may antagonize the tumor-promoting actions of estradiol in this model of mammary tumorigenesis.
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PMID:Pineal melatonin inhibition of tumor promotion in the N-nitroso-N-methylurea model of mammary carcinogenesis: potential involvement of antiestrogenic mechanisms in vivo. 174 57

We studied the effect of a progestin (lynestrenol) on estrogen receptors (ER) and cathepsin D (cath-D) levels immunochemically in successive fine needle aspirates of benign breast disease. Fibrocystic disease was the main pathology (43 out of 47 patients). Thirty-one patients were treated with 10 mg of lynestrenol daily from the fifth to the twenty-fifth day of the menstrual cycle for 1 to 3 months. Sixteen untreated patients were used as controls. Lynestrenol significantly decreased the percentage of ER stained cells. This is in agreement with the antiestrogenic effect of progestin and, for the first time, indicates that in vivo progestin may decrease the stimulatory effect of estrogens on mammary cells by decreasing their estrogen receptor content. No effect of progestin on cath-D level was found throughout the whole population. However, this level varied more between aspirates of each patient in the treated group than in the control group, suggesting heterogeneity in patient responses to progestin. Since cath-D may have a role in carcinogenesis, clinical follow-up of these patients and more detailed studies are required to determine whether this progestin-challenge test has any value for detecting high risk mastopathies and for predicting effectiveness of treatment.
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PMID:Progestin treatment depresses estrogen receptor but not cathepsin D levels in needle aspirates of benign breast disease. 175 73

The estrogen receptor in bilateral breasts of 36 6 to 10-month fetuses (17 male, 19 female) were examined. All fetal breasts had ER positive cells (greater than 50-90%). The ER levels were similar regardless of sex and age. When the ER status of 84 female breast cancer patients was analysed, ER was considered as an essential but not the only etiologic factor in mammary carcinogenesis. A positive correlation between the degree of differentiation and the ER level of breast cancer cells was demonstrated and the ER level did not correlate with the clinical staging of breast cancer. The results are briefly discussed in relation to the rationale of hormonal therapy of breast cancer.
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PMID:[Fetal breast estrogen receptor (ER) and breast cancer]. 178 45


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