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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oestrone sulphatase may be an important means of production of intra-tumoural oestrogens in breast cancer cells. The N-nitrosomethylurea induced rat mammary tumours, which is a good model of human breast carcinoma, was utilised to examine the significance of intra-tumoural oestrone sulphatase levels. The particular fraction (100,000 g pellet) was prepared from both the liver and the tumour of NMU treated rats and assayed for sulphatase activity. The tumour enzyme had an optimum pH of 7.2, Km value of 14.8 microM and Vmax of 0.90 nmoles min-1 mg-1, while the hepatic enzyme was optimal at pH 7.4, Km of 10.8 microM and Vmax of 3.71 nmoles min-1 mg-1. The relationship of intra-tumoural sulphatase levels with tumour regression and progression in endocrine responsive tumours was investigated. Tumour regression as a result of oophorectomy was associated with a significantly decreased intra-tumoural sulphatase level (mean level = 0.165 nmoles min-1 mg-1) in comparison to a control group (mean level = 0.319 nmoles min-1 mg-1, P less than 0.05) in which the tumours remained stable. This significant difference was not observed in the corresponding hepatic samples suggesting that it is the intra-tumoural rather than the peripheral production of oestrogens by oestrone sulphatase that is important in supporting growth of endocrine responsive tumours.
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PMID:Oestrone sulphatase activity in mammary tumours and the liver of N-nitrosomethylurea treated rats. 173 43

The biological role of transforming growth factor-alpha (TGF-alpha) in basal and hormone-stimulated proliferation of primary human and rat mammary tumor cells was studied using antibodies against TGF-alpha and its receptor. A monoclonal antibody, MAb-425 against human EGF receptor was added to in vitro soft agar, clonogenic cultures of human breast carcinoma cells under basal and estradiol(E2)-stimulated conditions. The antibody had an antagonist effect on colony growth in 4 of 10 tumors and an agonist effect in 4 (72 and 153% of control). E2-stimulated colony growth in 5 tumors (167% of control) and the antibody blocked E2-stimulation in 3 of the 5. Inhibition of E2-stimulated growth in 3 and basal growth in 4 other tumors by the EGF receptor antibody suggest that endogenously secreted TGF-alpha has a role as an autocrine/paracrine growth factor in constitutive and E2-stimulated tumor cell proliferation in a majority of human tumors. A polyclonal antibody against TGF-alpha was used to study the role of TGF-alpha in E2-, prolactin(Prl)- and progesterone(Prog)-stimulated proliferation of NMU(nitrosomethylurea)-induced rat mammary tumor cells under similar culture conditions. TGF-alpha, E2, Prl and Prog stimulated colony growth equally to 176, 187, 168 and 181% of control. The antibody produced significant and similar inhibition of TGF-alpha and E2-stimulated growth (95 and 83%). In contrast, inhibition of Prl- and Prog-stimulated growth by the antibody was only 24 and 37%. The TGF-alpha ligand antibody did not have an agonist or antagonist effect when added alone. Thus, TGF-alpha seems to be a major stimulatory growth factor mediating E2-induced tumor cell proliferation in rat mammary tumors. It is less important in Prl- and Prog-induced tumor growth and not essential for basal growth in these tumors. We conclude that TGF-alpha is a biologically important autocrine/paracrine growth factor in primary human breast cancer cell proliferation and in E2-induced rat mammary tumor growth.
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PMID:Role of transforming growth factor-alpha (TGF-alpha) in basal and hormone-stimulated growth by estradiol, prolactin and progesterone in human and rat mammary tumor cells: studies using TGF-alpha and EGF receptor antibodies. 206 83

The progesterone antagonists Onapristone (ZK 98.299) and Mifepristone (RU 486) proved to be strong inhibitors of various rodent mammary tumors. Therefore, a further potent antiprogestin, ZK 112.993, and 11 beta-(4-acetyl-phenyl)-analog of Mifepristone, with a high progesterone receptor affinity was tested in experimental rodent and human breast cancer models. In the hormone-dependent MXT(+) mammary tumor of the mouse, treatment of tumors immediately after implantation with 5 mg/kg for 6 weeks led to an inhibition of growth by 95%, being significantly superior to that caused by tamoxifen, diethylstilbestrol and Onapristone. Treatment of established MXT(+) tumors by ZK 112.993 at doses of 0.5, 1.0 and 2.0 mg/kg led to a strong inhibition that equalled that of ovariectomy and surpassed that of Onapristone in the lower doses. In the human, receptor positive mammary carcinoma T61 implanted in male, castrated nude mice, ZK 112.993 (10 mg/kg) significantly retarded tumor growth. Its effect was again superior to Onapristone though weaker than that of tamoxifen. The NMU-induced mammary carcinoma of the rat (established tumors) was inhibited by ZK 112.993 (5 and 10 mg/kg) in a dose-dependent manner slightly superior to Onapristone but weaker than after ovariectomy. Due to its strong antitumor activity and because of the innovative mechanism of action of antiprogesterones in tumor treatment, ZK 112.993 could be of great value for the treatment of breast cancer.
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PMID:Tumor-inhibiting potential of ZK 112.993, a new progesterone antagonist, in hormone-sensitive, experimental rodent and human mammary tumors. 236 83

In subcellular fractions of human mammary tumours and NMU tumours of rats proteinase activity was studied by means of the synthetic substrates Bz-dl-arginin-4-nitroanilid (BAPNA) and Bz-dl-arginin-2-naphthyl-amid (BANA). Using the substrate BAPNA enzymatic activity was found to be highest in low speed particulate fractions, whereas in NMU tumours of rats the bulk of the activities could be observed in the high speed supernatant. The substrates BAPNA and BANA were cleavaged enzymatically in human mammary tumours at pH 7 and pH 6, respectively, while in rats the maximum turnover of both substrates changed at value of pH 6.5. Enzyme activity with BAPNA was proved to be resistant to alkaline preincubation in human breast cancer tissue only. On the other hand, the enzymatic cleavage of BANA was completely lost in human as well as in rat tumour specimens under these experimental conditions. It can be concluded from these results that both enzyme activities measured in human malignant mammary tumours, which are known for their invading activity, represent two different proteolytic enzymes with their maximum activity at neutral and acidic pH. Similar enzyme activities are quite different in NMU tumours, which are not invasive.
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PMID:Proteinase activity in malignant human breast cancers and NMU mammary tumours of the rat. 283 1

A variety of clinical and experimental evidence indicates that the oestrogens are the major hormones affecting human breast cancer growth. The goal of recent treatment strategies is to reduce the amount of oestradiol acting locally on the tumour. For this reason, it is relevant to examine what determines tumour tissue oestradiol concentrations. Various steps are potentially important and include glandular or extraglandular production of oestradiol, tissue uptake, binding to receptors and the rate of local tissue oestradiol synthesis. In premenopausal women, glandular secretion of oestradiol by the ovary provides the major source of tissue oestradiol. In postmenopausal women, the extraglandular conversion of androstenedione to oestrone and then oestradiol in peripheral tissues accounts for 90% of circulating oestradiol. However, plasma levels of oestradiol in postmenopausal women are only 4 to 40% of those found in premenopausal patients and yet breast cancer tissue levels are similar. This observation suggests the possibility of local oestradiol synthesis by breast tumours in postmenopausal women. We examined two pathways which could be involved in local oestradiol synthesis: the androstenedione to oestrone (aromatase) pathway and the oestrone-sulphate to oestrone (sulphatase) system. Seventy-nine of 128 tumours contained aromatase with activity ranging from 5-80 pmol/g protein/hr. This enzyme was of high affinity with a Km of 0.027 microM. Sulphatase, on the other hand, was present in all tumours with activity ranging from 0.8-125 microM. Its affinity was appreciably lower with a Km of 27 microM. Comparing both activities at substrate concentrations approaching physiological levels, we detected 10-fold higher activity with sulphatase than with aromatase. Further studies revealed the presence of 17 beta-hydroxysteroid dehydrogenase in all tumors studied. Whereas 50% of tissues contained both a high and a low affinity type of activity, the remainder had only the low activity form. Since our data favoured the oestrone-sulphate to oestrone to oestradiol pathway as biologically relevant, we sought to determine whether oestrone-sulphate could act as an oestrogen after conversion to oestradiol. Using an NMU rat mammary tumour soft agar colony forming assay, we found that oestrone-sulphate stimulated colony growth in a manner consistent with its 1% conversion to oestradiol by cells in the agar dishes. Furthermore, preliminary data indicate that oestrone-sulphate can stimulate NMU tumour growth in vivo in rats. The metabolism of oestradiol in tissue can also determine its biological effects and its tissue levels.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Determinants of tissue oestradiol levels in human breast cancer. 355 85

Inhibition of aromatase to reduce estrogen production by peripheral and ovarian tissue could be a useful approach to treating hormone-dependent breast cancer. Several C19, 17 keto steroids have been identified as aromatase inhibitors. The most potent of these cause rapid competitive inhibition followed by enzyme inactivation. Injections of the compounds caused inhibition of peripheral aromatization in monkeys. In rats, these treatments result in inhibition of ovarian aromatase and estrogen secretion, accompanied by marked regression of carcinogen(DMBA or NMU)-induced mammary tumors. To date, 60 postmenopausal patients with advanced metastatic breast cancer and unselected for the presence of estrogen receptors have been treated with once weekly injections of 4-OHA. The mean estradiol level measured in 14 patients was significantly reduced to 36% of pretreatment values after 1 month and remained at this level for up to 4 months. There was no effect of treatment on gonadotropin levels. Although all patients had relapsed from previous therapy, complete or partial tumor regression occurred in 30% of patients while 15% had static disease. The results indicate that in these patients the responses are due to inhibition of peripheral aromatization and that 4-OHA may be of value in treating postmenopausal breast cancer.
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PMID:Aromatase inhibitors and the treatment of breast cancer. 370 31

While hormone-dependent, mammary tumors induced with carcinogens (DMBA or NMU) in intact rats have been used extensively for studying aromatase inhibitors, there is currently no suitable model to investigate their effects in human breast cancers in vivo. While hormone responsive tumors can be formed in the athymic mouse using human breast carcinoma MCF-7 cells, due to the low ovarian estrogen production, tumor growth is induced with estradiol supplementation. Thus, this model is unsuitable for studies of aromatase inhibitors. We have induced tumors without the need for estrogen supplementation by co-inoculating MCF-7 cells with Matrigel, a basement membrane preparation, into intact athymic mice. In one experiment, 45 days after inoculation, mice were assigned to the control group or 4-hydroxyandrostenedione (4-OHA) (1 mg/day s.c.) treatment for 52 days. Tumor volumes in the control mice increased 672%, whereas tumor volumes in the treated mice did not change significantly (178.9 +/- 16.2 to 336.6 +/- 120 mm3). In the second experiment, 55 days after inoculation, groups of mice were treated with the antiestrogen, tamoxifen (5 micrograms/day s.c.) or vehicle (controls). Tumor volumes in the control mice increased 325% in 58 days, whereas there was no significant change in tumor volume in the tamoxifen treated group (338.8 +/- 55.3 to 330.6 +/- 84.9 mm3). The results suggest that (1) the tumors resulting from MCF-7 cells co-inoculated with Matrigel are estrogen-dependent and (2) tamoxifen and 4-OHA were effective in suppressing growth of these tumors. The results suggest that this model should be useful for evaluating the effects of aromatase inhibitors and for comparing breast cancer treatments.
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PMID:MCF-7 human breast carcinomas in nude mice as a model for evaluating aromatase inhibitors. 847 81

The breast cancer gene BRCA1 has previously been cloned from both human and mouse. We cloned a fragment of the rat Brca1 homologue in order to map it and explore its biological function. Partial cDNA fragments of the rat Brca1 homologue were isolated by RT-PCR. Sequence analysis revealed that the RING-finger domain is well conserved among rat, mouse and human. Rat Brca1 mRNA was expressed in most tissues studied with the highest level in testis, consistent with studies in human and mouse. Next, intron 6-containing DNA fragments were amplified by PCR from WKY and WF rat strains. The splicing sites between exon 6 and exon 7 are conserved between rat and human. Partial sequencing of the rat Brca1 intron 6 revealed a polymorphism of a pentanucleotide TTTTG repeat between the WKY and WF strains. With this intragenic microsatellite marker, we were able to map precisely the rat Brca1 gene to chromosome 10 using a genetic linkage study of (WKY x WF)F1 x WF backcross rats. Brca1 cosegregates with marker BAND3A, and is flanked by R5123 and R5842. Using this polymorphic marker, we also investigated the loss of heterozygosity (LOH) of the Brca1 microsatellite marker in carcinogen- or radiation-induced mammary carcinomas in (WF x F344)F1 female rats. No LOH or somatic microsatellite instability was detected in 18 DMBA-induced tumors studied. Only one LOH of the F344 allele was observed in 26 radiation-induced tumors tested. Ribonuclease protection assays demonstrated that Brca1 mRNA levels are similar in normal rat mammary glands and mammary carcinomas of various etiologies, including those induced by DMBA, NMU, activated-neu and activated-ras oncogenes.
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PMID:Cloning, genetic mapping and expression studies of the rat Brca1 gene. 876 10

Previously we have shown that exercising rats prior to administration of 50 mg NMU/kg (high dose) significantly decreased tumor multiplicity, but not incidence or latency. We hypothesized that the dose of NMU saturated the system such that the exercise intervention was overshadowed. Therefore, the purpose of this investigation was to determine if exercise would have a more pronounced effect with a moderate dose of 37.5 mg NMU/kg. Female Sprague Dawley rats were divided into sedentary and exercised groups. The rats were exercised five times per week from 21 to 50 days of age on a progressive treadmill training program with a final workload of 18 m/min at 15% incline for 60 min a day. At 50 days of age all rats were given an i.p. injection of NMU at 37.5 mg/kg body weight. The experiment was terminated 22 weeks post carcinogen administration. Although there was no difference in terms of tumor incidence, multiplicity, or latency between the two groups, the tumor growth rate (0.107+/-0.025 vs. 0.043+/-0.009 g/day) and final tumor weight (3.2+/-0.74 vs. 1.2+/-0.34 grams) were significantly higher in the exercised animals. IGF-I receptor (9.4+/-96 vs. 10.5+/-57 per microg protein) and estrogen receptor (18.4+/-1.14 vs. 19.6 + 1.6 per microg protein) levels were not significantly different in tumors from exercised animals compared to those from sedentary animals. For both sets of tumors, correlation between estrogen receptor content and growth rate is positive, while the correlation between IGF-I receptor content and growth rate is negative. The results of this study suggest that exercise prior to NMU administration does not affect tumor burden but does alter tumor growth rate, which is not due to differences in estrogen receptor or IGF-I receptor content.
Breast Cancer Res Treat 1998 Jan
PMID:Exercise during puberty and NMU induced mammary tumorigenesis in rats. 949 70

We have established a newly derived breast cell line, called G8. This line was obtained by means of the neoplastic transformation of murine breast cells through exposure to the carcinogen NMU and its subsequent inoculation in athymic nude mice. This cell line is highly tumorigenic in nude mice. The tumors that developed in the mice were mammary adenocarcinomas. The morphological and ultrastructural pattern suggested that these cells are of epithelial origin. Immunocytochemical studies revealed that the cells express desmoplakin, vimentin, epithelial membrane antigen, fibronectin and actin. The possibility of maintaining this cell line in vivo by means of xenografts provides very valuable material for breast cancer research, as not only does tumor growth in vivo provide the ideal material for the testing of new therapies, but it also enables the study of various important interactions between the tumor and the host tissues including tumor-stroma interactions such as angiogenesis.
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PMID:A new breast cancer cell line of epithelial origin is tumorigenic in athymic mice. 967


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