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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogens induce kidney tumors in Syrian hamsters. The mechanism of carcinogenesis is unknown and has been investigated in this study using a weak carcinogen, 17 alpha-ethinyl estradiol (EE), and a strongly carcinogenic estrogen, 17 alpha-ethinyl-11 beta-methoxyestradiol [moxestrol (MOX)]. We investigated rates of conversion of estrogens to catechol metabolites and rates of their methylation to methyl ethers in order to examine the hypothesis that catechol metabolites mediate estrogen-induced carcinogenesis. Rates of conversion of MOX to catechol metabolites by hamster liver or kidney cortex microsomes were 40-50% of those with estradiol as substrate. However, the rate of catechol-O-methyltransferase-catalyzed methylation of 2-hydroxy-MOX was the least of the catechol metabolites examined when incubated with cytosol of hamster kidney. In contrast, EE was converted to catechol metabolites by hamster liver and kidney microsomes at rates 25-35% of those obtained with estradiol. These catechol metabolites of EE were methylated by catechol-O-methyltransferase of hamster kidney cytosol at rates slightly lower than those observed with catechols of estradiol. The progesterone receptor binding of EE and MOX was investigated, because progesterone is known to inhibit estrogen-induced carcinogenesis in the hamster kidney. Neither estradiol nor MOX inhibited the binding of progesterone to its receptor in hamster kidney cytosol. However, in the presence of 20 nM EE, the binding affinity of radiolabeled progesterone to receptor was inhibited (increase in Kd from 0.98 nM in controls to 3.02 nM in the presence of EE). Maximum binding values (5.0 fmol/mg protein in controls and 6.0 fmol/mg protein in the presence of EE) were not significantly altered. These results support the hypothesis that estrogen-induced carcinogenesis is mediated by catechol estrogen metabolites. The carcinogenic estrogen MOX is converted to catechol metabolites at lower rates than estradiol, but their methylation may be sterically hindered by the 11 beta-methoxy substituent. In contrast, the rates of conversion of the weakly carcinogenic EE to catechol metabolites are low, whereas their methylation rates are only marginally lower than those of 2- and 4-hydroxyestradiol. The decreased capacity of EE to form catechol metabolites in conjunction with its partial progestin agonist activity in the target organ of hamsters may contribute to the low tumor incidence.
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PMID:The carcinogenic activity of ethinyl estrogens is determined by both their hormonal characteristics and their conversion to catechol metabolites. 838 Oct 68

Estrogens are considered to act as promoters in a multistep process of hormonal carcinogenesis, although the molecular mechanisms by which these hormones act in tumorigenesis are unclear at present. Estradiol is known to induce expression of certain proto-oncogenes, and this led us to examine potential regulatory regions of the cellular c-fos oncogene. The 5'-flanking region of the murine c-fos contains a 13-bp palindromic sequence (GGTCTnnnAGACC) with striking homology to the consensus estrogen-responsive element (ERE) GGTCAnnnTGACC. However, the c-fos sequence did not bind the human estrogen receptor or confer hormonal responsiveness in a yeast-based transcriptional test system. Importantly, a single base change in the fifth position of the c-fos sequence (GGTCTnnnAGACC to GGTCA/GnnnAGACC) produced an element that bound the estrogen receptor and conferred estrogen-dependent transcriptional activation of a reporter gene. This suggests a specific hypothesis by which estrogens could act as tumor promoters. In this paradigm, the regulatory region of the cellular oncogenes, tumor suppressor genes, and growth-factor genes contain inactive sequences with close homologies to hormone-responsive elements. Initiation occurs when some agent (e.g., a chemical carcinogen) causes a mutation in such a sequence to create a functional hormone-responsive element. Estrogens, acting through their receptors and the mutated element, can then activate the target gene to stimulate cell proliferation and increase the population of initiated cells.
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PMID:Creation of an active estrogen-responsive element by a single base change in the flanking sequence of a cellular oncogene: a possible mechanism for hormonal carcinogenesis? 845 91

Sequential estrogen and radiation therapy was introduced to improve treatment result for stage C of the prostate cancer. Staging operation was performed in order to exclude stage D1 cases at the beginning of the treatment. Twenty of 34 stage C cases have been treated by sequential estrogen and radiation in our hospital between 1980 and 1989 and half of them had actually been done staging operation. An average age was 69.3. Tumor differentiations were distributed to well in 5 cases, moderately in 5 and poorly in 9. The other unknown differentiation case was diagnosed by fine needle aspiration cytology. Previously administered estrogens were DES-DP in 15 cases and others in 5. Total doses of 70 Gy in 35 fractions were sequentially delivered to the prostate, involving if necessary the seminal vesicles over a seven-week period by bilateral 120 degrees pendel using linear accelerator. Radiation field was sized from 6 x 6 to 8 x 8 cm. Estrogens have been continuously administered following radiation in 11 cases. Therapeutic effects upon the prostate were evaluated by digital rectal palpation. Improvement rate and atrophy rate of the primary lesion were 94.4% and 50% respectively. Recurrences were observed in 4 cases and 3 of them recurred within 3 years after initiation of the treatment. Recurred sites were in primary lesion in 2 cases and in bone in two. Five year non-recurrence rate was 81% by Kaplan Meier's method. One of 3 who discontinued hormone administration during or immediately after radiotherapy had local recurrence after 65 months and the other 2 cases died of gastric cancer and unknown cause, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Sequential estrogen and radiation therapy for stage C prostate cancer]. 851 32

In this report, we have discussed a series of results obtained in our laboratory that, together with data by other authors, demonstrate that the expression of the erbB-2 tyrosine kinase receptor oncogene in breast cancer cells is regulated by multiple factors and hormones, which modulate their growth and differentiation. In particular, we have shown that estrogens specifically inhibit erbB-2 expression by transcriptional repression, which is exerted through a sequence within the erbB-2 gene promoter. Estrogens control mammary cell growth directly, by inducing early gene expression, and indirectly, by increasing autocrine growth factor production or decreasing growth inhibitors. The data presented here suggest that mammary cells respond to estrogen also by modifying the receptor array on their surface, thus setting their own sensitivity to the different autocrine and paracrine factors. As a first consequence, the modulation of erbB-2 expression level by antiestrogen may represent a point to consider when selecting breast cancer patients for hormonal therapy, in those (few) cases where estrogen receptor positivity accompanies erbB-2 amplification. On the other hand, antiestrogen-induced upregulation of erbB-2 may improve tumor targeting of drugs designed to interact or interfere with erbB-2, such as humanized antibodies, immunotoxins, or engineered ligands. These possibilities should be tested in appropriate model systems in the future.
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PMID:Hormonal control of growth factor receptor expression. 865 82

Estrogens promote adenohypophyseal enlargement and tumor transformation, and thyroid hormones antagonize these effects. Hormone-induced pituitary enlargement may be mediated by alterations in pituitary dopaminergic function. The present study examined the effects of chronic (20 days) administration of estradiol benzoate (EB), triiodothyronine (T3), or EB and T3 (T3 + EB) on dopamine (D-2) receptors in rat anterior pituitary. D-2 receptor number increased after EB without altered receptor affinity. T3 alone did not affect D-2 receptor number in the anterior pituitary but significantly attenuated the effect of EB. T3 administration also inhibited EB-induced anterior pituitary hyperplasia. D-2 receptor upregulation by EB more likely could reflect a compensatory response to decreased receptor occupation. The present results suggest that D-2 receptors could play an important role in estrogen-induced adenohypophyseal tumor formation and hyperprolactinemia and that thyroid hormones may inhibit estrogen-induced pituitary tumor development via adenohypophyseal D-2 receptors.
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PMID:Triiodothyronine attenuates estradiol-induced increases in dopamine D-2 receptor number in rat anterior pituitary. 870 98

The demonstration of estrogen receptors (ERs) in the liver has established it as a hormonally responsive organ. Estrogens have been imputed to have a role in the development of benign and malignant liver tumors. The detection of ERs in samples of normal liver tissue and in hepatocellular carcinomas suggested a treatment strategy with anti-hormonal drugs, i.e. tamoxifen, as used clinically for the treatment of breast cancer. The objective of this study was to test the effect of tamoxifen and tamoxifen in combination with other agents [5-fluorouracil (5-FU) and interferon (IFN)] against experimental liver metastases of human colorectal tumor cells xenografted into nude mice. A human colorectal tumor cell line, LoVo, was injected into the spleens of nude mice. This produces liver metastases in virtually 100% of the mice in 6-8 weeks. One week before tumor cell implantation, all mice were ovariectomized. Treatment was started 3 days after the intrasplenic injections. This consisted of 5 mg tamoxifen pellets (60-day release) implanted s.c., 5-FU given i.p. once a week for 4 weeks on a 46 mg/kg basis and IFN given s.c., daily for 4 weeks, 3 x 10(5) units/injection. The effect of tamoxifen alone on liver metastases was not significantly different from untreated controls. Tamoxifen in combination with IFN and 5-FU, however, resulted in 50-67% inhibition of liver metastases, as compared with the controls. The effectiveness of the treatment was in the order: tamoxifen + IFN > tamoxifen + 5-FU + IFN > tamoxifen + 5-FU. Thus, IFN may be useful as a potentiating agent in combination with tamoxifen for the treatment of estrogen-dependent tumors.
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PMID:Inhibition of experimental liver metastasis by combined treatment with tamoxifen and interferon. 879 5

Retinoids modulate gene activity, cell growth and differentiation by binding to a series of nuclear receptors, i.e., retinoic acid receptors (RARs) or retinoid X receptors. Retinoic acid (RA) inhibition of estrogen receptor (ER)-positive breast carcinoma seems to be mediated through RAR alpha. Estrogens upregulate RAR alpha in ER-positive breast carcinoma cell lines. In this study we examined RAR alpha expression in the ER-positive MCF7 and ER-negative MDA-MB-231 human breast carcinoma cell lines as well as in 10 ER-negative and 9 ER-positive infiltrating ductal breast carcinoma specimens using immunohistochemistry and quantitation by image cytometry. MCF7 cells expressed twofold higher levels of RAR alpha protein than MDA-MB-231 cells. RAR alpha expression, as detected by immunostaining and quantitated by image cytometry, was upregulated in these cells by estradiol. ER-positive breast carcinoma specimens also exhibited approximately two-fold higher RAR alpha levels than their ER-negative counterparts. Thus, RAR alpha expression is significantly elevated in ER-positive breast tumors as assessed by detection and quantitation using immunohistochemical staining and image cytometry, respectively. Whether the decrease in RAR alpha protein levels and loss of RA-mediated growth inhibition in ER-negative tumor plays a role in the increased metastatic potential of ER-negative tumors remains to be determined.
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PMID:Elevated expression of retinoic acid receptor-alpha (RAR alpha) in estrogen-receptor-positive breast carcinomas as detected by immunohistochemistry. 902 36

Estrogens are risk factors for human breast cancer and induce kidney tumors in Syrian hamsters. Mechanistic features of the estrogen-induced hamster kidney tumor model have been compared with corresponding aspects of human breast cancer to gain insight into the mechanism of human mammary oncogenesis. Shared characteristics point to a mechanism of metabolic activation of steroidal estrogens to 4-hydroxylated catechol metabolites that may undergo metabolic redox cycling, a mechanism of generation of reactive free radicals. Tumors may arise in cells genetically altered by various types of estrogen-induced DNA damage. At the same time, these altered cells may respond to estrogen receptor-mediated stimuli in support of cell transformation and growth.
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PMID:Hormone-associated cancer: mechanistic similarities between human breast cancer and estrogen-induced kidney carcinogenesis in hamsters. 916 96

Estrogens, which have been associated with several types of human and animal cancers, can induce tumor angiogenesis in the pituitary of Fischer 344 rats. The mechanistic details of tumor angiogenesis induction, during estrogen carcinogenesis, are still unknown. To elucidate the role of estrogen in the regulation of tumor angiogenesis in the pituitary of female rats, the density of blood vessels was analysed using factor VIII related antigen (FVIIIRAg) immunohistochemistry and the expression of vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) was examined by Western blot and immunohistochemical analysis. The expression of VEGF receptor (VEGFR-2/Flk-1/KDR) was also examined by immunohistochemistry. The results demonstrated that 17beta-estradiol (E2) induces neovascularization, as well as the growth and enlargement of blood vessels after 7 days of exposure. The high tumor angiogenic potential was associated with an elevated VEGF/VPF protein expression in the E2 exposed pituitary of ovariectomized (OVEX) rats. VEGF/VPF and FVIIIRAg immunohistochemistry and endothelial specific lectin (UEA1) binding studies, indicate that the elevation of VEGF protein expression initially occurred in both blood vessels and non-endothelial cells. After 15 days of E2 exposure, VEGF/VPF protein expression, in the non-endothelial cell population, sharply declined and was restricted to the blood vessels. The function of non-endothelial-derived VEGF is not clear. Furthermore, immunohistochemical studies demonstrated that VEGFR-2 (flk-1/KDR), expression was elevated significantly in the endothelial cells of microblood vessels after 7 days of E2 exposure. These findings suggest that over expression of VEGF and its receptor (VEGFR-2) may play an important role in the initial step of the regulation of estrogen induced tumor angiogenesis in the rat pituitary.
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PMID:Over expression of vascular endothelial growth factor and its receptor during the development of estrogen-induced rat pituitary tumors may mediate estrogen-initiated tumor angiogenesis. 921 97

Although oncogenes are involved in tumor development and progression, their activation during human ontogenesis is inseparably associated with normal fetal development. The c-erbB-2-encoded oncoprotein p185 (HER-2/neu) is overexpressed on fetal epithelial cells, in the placenta, and in several human carcinomas. In patients with p185-overexpressing tumors and in pregnant women at term, increased serum levels of a 105 kDa proteolytic breakdown product corresponding to the extracellular domain of oncoprotein p185 are detectable. Estrogens have been described to be potent inhibitors of p185 expression in human breast cancer cells and to influence also p105 serum levels in females. Regarding the significantly poorer prognosis of patients with c-erbB-2-positive tumors, we discuss common features and differences between c-erbB-2 oncoprotein overexpression in pregnancy and in carcinogenesis.
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PMID:Expression of the c-erbB-2-encoded oncoprotein p185 (HER-2/neu) in pregnancy as a model for oncogene-induced carcinogenesis. 968 12


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