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

The animal models for chemoprevention of breast cancer have provided important experimental systems to evaluate the efficacy of tumor suppression by dietary macro- and micronutrients. In the initiation/promotion cascade, early occurring premalignant changes constitute less extensively examined aspects of disease progression. Molecular, endocrine and cellular biomarkers may provide clinically relevant endpoints for prevention of breast cancer that focus on downregulation of preneoplastic transformation. In vitro models derived from non-involved murine and human mammary tissues are utilized to identify molecular, endocrine and cellular markers that are perturbed in response to such diverse initiators as viruses and chemical carcinogens. This upregulation was manifested as persistent Ras p21-GTP binding, altered C16 alpha/C2 hydroxylation of estradiol, and hyperplasia preceding tumorigenesis. Prototypic chemopreventive agents such as n-3 polyunsaturated fatty acids, retinoids, and indole-3-carbinol were capable of downregulating all of the preneoplastic markers perturbed by initiators. Experimental modulation of these biomarkers in murine and human mammary tissue prior to the expression of a fully transformed tumorigenic phenotype is suggestive of their potential clinical application in chemopreventive intervention for breast cancer.
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PMID:Molecular and endocrine biomarkers in non-involved breast: relevance to cancer chemoprevention. 146 96

Research studies have demonstrated a strong association between estrogen metabolism and the incidence of breast cancer, and we have therefore sought pharmacological means of favorably altering both metabolism and subsequent risk. Indole-3-carbinol (I3C), obtained from cruciferous vegetables (e.g., cabbage, broccoli, etc.), is a known inducer of oxidative P-450 metabolism in animals. We investigated the effects in humans of short-term oral exposure to this compound (6-7 mg/kg/day over 7 days). We used an in vivo radiometric test, which provided a highly specific and reproducible measure of estradiol 2-hydroxylation before and after exposure to I3C. In a group of 12 healthy volunteers, the average extent of reaction increased by approximately 50% during this short exposure (p less than 0.01), affecting men and women equally. We also measured the urinary excretion of two key estrogen metabolites, 2-hydroxyestrone (2OHE1) and estriol (E3). We found that the excretion of 2OHE1 relative to that of E3 was significantly increased by I3C, further confirming the ongoing induction of 2-hydroxylation. These results indicate that I3C predictably alters endogenous estrogen metabolism toward increased catechol estrogen production and may thereby provide a novel "dietary" means for reducing cancer risk.
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PMID:Altered estrogen metabolism and excretion in humans following consumption of indole-3-carbinol. 165 96

Dietary indoles in cruciferous vegetables induce cytochrome P450 enzymes and have prevented tumors in various animal models. Because estradiol metabolism is also cytochrome P450 mediated and linked to breast cancer risk, indoles may similarly reduce estrogen-responsive tumors in humans. We examined several indoles in female Sprague-Dawley rats for induction of hepatic estradiol 2-hydroxylation. The most potent inducer, indole-3-carbinol, was administered to humans (500 mg daily for 1 wk). It significantly increased the extent (mean +/- SEM) of estradiol 2-hydroxylation from 29.3% +/- 2.1% to 45.6% +/- 2.1% (P less than .001). These results indicate that indole-3-carbinol strongly influences estradiol metabolism in humans and may provide a new chemopreventive approach to estrogen-dependent diseases.
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PMID:Induction of estradiol metabolism by dietary indole-3-carbinol in humans. 163 91

It has been hypothesized that organochlorine pesticides and other environmental and dietary estrogens may be associated with the increased incidence of breast cancer in women and decreased sperm concentrations and reproductive problems in men. However, elevation of organochlorine compounds such as dichlorodipehenyldichloroethylene (DDE) and polychlorinated biphenyls (PCBs) in breast cancer patients is not consistently observed. Reanalysis of the data showing that male sperm counts decreased by over 40% during 1940 to 1990 indicated that inadequate statistical methods were used and that the data did not support a significant decline in sperm count. Humans are exposed to both natural and industrial chemicals which exhibit estrogenic and antiestrogenic activities. For example, bioflavonoids, which are widely distributed in foods, and several industrial compounds, including organochlorine pesticides and various phenolic chemicals, exhibit estrogenic activity. Humans are also exposed to chemicals which inhibit estrogen-induced responses such as the aryl hydrocarbon receptor (AhR) agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin and related chlorinated aromatics, polynuclear aromatic hydrocarbon combustion products, and indole-3-carbinol, which is found in cruciferous vegetables. Many of the weak estrogenic compounds, including bioflavonoids, are also antiestrogenic at some concentrations. A mass balance of dietary levels of industrial and natural estrogens, coupled with their estimated estrogenic potencies, indicates that the dietary contribution of estrogenic industrial compounds is 0.0000025% of the daily intake of estrogenic flavonoids in the diet.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Environmental and dietary estrogens and human health: is there a problem? 749 80

Indole-3-carbinol, a component of cruciferous vegetables, was evaluated for it efficacy in the prevention of chemically-induced mammary tumors using three different protocols. Because this compound was unstable, it was administered by gavage rather than in the diet. A preliminary dose range study revealed that dose levels of 100 and 50 mg/day, 5x/week, were not toxic to female Sprague-Dawley rats. Initial studies in the DMBA model showed that administering indole-3-carbinol during the initiation and promotion phases were highly effective chemopreventive methods (91-96% reduction in cancer multiplicity). Subsequent studies showed that the administration of indole-3-carbinol only during the initiation phase (7 days prior to until 7 days post DMBA) was also highly effective as a chemopreventive agent. Determination of enzyme levels in the livers of animals treated long-term with indole-3-carbinol showed high levels of induction of various phase I and phase II drug metabolizing enzymes. Finally, indole-3-carbinol when administered both prior to and after MNU (a direct acting carcinogen) caused a significant decrease (65%) in mammary tumor multiplicity. These results support previous studies that indole-3-carbinol can prevent mammary carcinogenesis by direct and indirect acting carcinogens. Therefore, indole-3-carbinol might be a good candidate for chemoprevention of breast cancer in women.
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PMID:Chemoprevention of chemically-induced mammary carcinogenesis by indole-3-carbinol. 764 47

Anti-estrogenic effects of yuehchukene were observed in rat uterotrophic, mice vaginal smear and MCF-7 cell growth assays. Whereas yuehchukene per se was estrogenic in these bioassay models, the co-administration of yuehchukene and an optimal dose of 3,17 beta-estradiol (estradiol) could attenuate the maximum estrogenic response due to estradiol alone. The anti-estrogenic effect of yuehchukene in rat uterine hypertrophy was corroborated by a parallel attenuation of ornithine decarboxylase activity in these tissues. Yuehchukene binds to rat, mice and MCF-7 cell estrogen receptors with a relative binding affinity of 1/150 to 1/300. This binding affinity was positively related to estrogenicity as determined by uterotrophic assay and MCF-7 cell growth. However, this estrogenic effect did not correlate with the degree of competitive receptor binding by a weaker agonist. Indole-3-carbinol and methylbutadienylindole could induce ethoxyresorufin O-deethylase and estradiol-2-hydroxylase in rat liver and MCF-7 cells. It is postulated that the 'free' indole moiety of yuehchukene could possess similar induction activity. Thus yuehchukene may have a dual pharmacological function. While the intact molecule is a weak estrogen, the 'free' indole moiety in yuehchukene may induce an enhancement of estradiol-2-hydroxylase, thus terminating the biological activity of the endogenous estrogen pool. There is obvious benefit in attenuating the estrogen level in post-menopausal breast cancer patients without going directly to the use of tamoxifen or aromatase inhibitor. Yuehchukene may serve this purpose. In this context, the pharmacological evaluation of a hydroxylated yuehchukene analogue and the anti-estrogenic effect of methylbutadienylindole acid-condensation products are now being studied in earnest.
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PMID:Mixed estrogenic and anti-estrogenic activities of yuehchukene--a bis-indole alkaloid. 782 37

In mammals, estradiol (E2) metabolism primarily involves mutually exclusive hydroxylation at either C-2 or C-16 alpha. We have previously reported a consistent increase in the C-16 alpha hydroxylation activity in human breast cancer and in mouse strains with high levels of mammary tumors. Here we show that the dietary compound indole-3-carbinol (I3C) increases C-2 hydroxylation five-fold in MCF-7 cells in culture but has minimal effect on the reaction at C-16 alpha. Because I3C-induced changes in E2 metabolism result in a metabolite ratio inverse to that observed in women with breast cancer we have separately examined whether this shift conferred an anti-tumorigenic advantage to estrogen target cells. The preferential changes induced by I3C on estradiol metabolism in MCF-7 cells parallel its anti-tumorigenicity in mice. These results suggest that changes in the metabolism of estradiol via the C-2 pathway might play a significant role in decreasing risk for breast cancer in women. Indole-2-carbinol is readily available as a chemical and as a dietary component of cruciferous vegetables. Feasible dietary changes show promise of having clinical utility in the prevention of breast cancer and other hormone-dependent cancers.
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PMID:Alterations in estradiol metabolism in MCF-7 cells induced by treatment with indole-3-carbinol and related compounds. 784 34

Compounds like indole-3-carbinol (I3C) have been shown to increase catechol estrogen formation and reduce mammary tumor incidence in mice. These compounds may exert a protective effect for breast cancer development by decreasing the overall estrogen pool available for the formation of 16 alpha-hydroxyestrone (16 alpha-OHE1), a metabolite that retains significant estrogenic activity, may be mutagenic and could represent a potential carcinogenic intermediate of estradiol degradation. I3C and ascorbigen originate from the breakdown of glucobrassicin. We have compared the inductive effects of I3C with ascorbigen and beta-naphthaflavone (Bnf) in microsomes from rats pretreated with these compounds using isotope dilution GC-MS and a radiometric method. Incubated microsomes from rats pretreated with I3C and ascorbigen yielded high levels of 2-hydroxyestradiol (2-OHE2) that were comparable to levels induced by Bnf and were significantly above control group levels (p < 0.005). Absolute values determined by the radiometric method were approximately 40% lower than 2-OHE2 concentrations determined by GC-MS, although the relative changes in each group were the same. These differences may be attributed to the radiolabel becoming trapped in microsomal intermediates in the sequence leading to tritium entering the aqueous compartment. Both ascorbigen- and Bnf-treated animals exhibited significant increases in 2-hydroxyestrone (2-OHE1) (p < 0.05). The ability of ascorbigen to induce estradiol C-2 hydroxylation has not been previously reported. Based on these data, we speculate that ascorbigen will act as an anticarcinogenic agent and will inhibit or reduce the incidence of mammary tumor formation.
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PMID:Catechol estrogen production in rat microsomes after treatment with indole-3-carbinol, ascorbigen, or beta-naphthaflavone: a comparison of stable isotope dilution gas chromatography-mass spectrometry and radiometric methods. 807 45

The polycyclic aromatic hydrocarbon 7,12-dimethylbenz(a)anthracene (DMBA) is a metabolism-dependent procarcinogen whose tumorigenicity is modified by dietary and endocrine manipulations in vivo. DMBA initiates molecular and cellular alterations in the mammary tissue, while dietary components and estrogens affect the post-initiational phase of tumorigenic transformation. The mechanism(s) responsible for modulation of tumorigenic transformation remain unclear. This study examines the effects of selected tumor suppressing agents and estradiol (E2) metabolites on in vitro DMBA carcinogenesis utilizing a newly established mouse mammary epithelial cell line C57/MG. Alteration in DNA repair synthesis, metabolism of E2 via the C2- and C16 alpha-hydroxylation pathways, and acquisition of anchorage-independent growth were utilized as molecular, endocrine, and cellular biomarkers to quantitate the cellular transformation by DMBA and its modulation by tumor suppressing agents and E2 metabolites. A single 24 hr exposure of 0.78 microM DMBA to C57/MG cells resulted in a 193.9% increase in DNA repair synthesis and a 73.1% decrease in C2/C16 alpha hydroxylation of E2. The DMBA treated C57/MG cells also exhibited increased anchorage-independence in vitro prior to tumorigenesis in vivo. A simultaneous treatment of cells with DMBA and with the highest noncytotoxic doses of the tumor suppressing agents 5 microM N-(4-hydroxyphenyl) retinamide (HPR), 50 microM indole-3-carbinol (I3C), or 1 microM tamoxifen (TAM) resulted in a 35.6% to 63.9% decrease in DNA repair synthesis, a 23.8% to 1347.6% increase in C2/C16 alpha hydroxylation of E2, and a 53.8% to 72.4% decrease in anchorage-independent growth. The E2 metabolites at the highest non-cytotoxic doses of 0.76 microM estrone (E1), 0.69 microM 2-hydroxyestrone (2-OHE1), and 0.66 microM 2-methoxyestrone (2-MeOHE1) suppressed DMBA-induced DNA repair synthesis by 56.0% to 68.8%. These tumor suppressing agents and E2 metabolites also effectively suppressed post-initiational, anchorage-independent growth by 24.9% to 72.4%. These results indicate that DMBA induces cellular transformation in part by causing DNA damage, altering C2/C16 alpha hydroxylation in favor of C16 alpha-hydroxylation, and inducing anchorage-independent growth prior to tumor development. Effective downregulation of these genotoxic, endocrine and proliferative end points by prototypic tumor suppressing agents and by E2 metabolites generated via the C2-hydroxylation pathway suggest that these agents may influence mammary tumorigenesis by inhibiting early occurring initiational and/or post initiational events.
Breast Cancer Res Treat 1993 Sep
PMID:Experimental down-regulation of intermediate biomarkers of carcinogenesis in mouse mammary epithelial cells. 831 77

Xenobiotic estrogens are external compounds with estrogenic activity that may thereby affect the risk of breast cancer. This paper describes a mechanism by which xeno-estrogens may affect the development of breast cancer. Estradiol metabolism proceeds by hydroxylation at one of two mutually exclusive sites at C-2 and C-16 alpha. The catechol pathway yields the weakly estrogenic 2-hydroxyestrone (2-OHE1), which inhibits breast cell proliferation. In contrast, the alternative pathway yields the genotoxic 16 alpha-hydroxyestrone (16 alpha-OHE1), which enhances breast cell growth, increases unscheduled DNA synthesis, and oncogene and virus expression, and increases anchorage-independent growth. Using a radiometric assay that measures the relative formation of 16 alpha-OHE1 versus 2-OHE1 from specifically tritiated estradiol in (ER+) MCF-7 cells, we compared the ratio of 16 alpha-OHE1/2-OHE1 observed after treatment with the known rodent carcinogen 7,12-dimethylbenz[a]anthracene (DMBA) with the ratios after treatment with DDT, atrazine, gamma-benzene hexachloride, kepone, coplanar PCBs, endosulfans I and II, linoleic and eicosapentenoic acids, and indole-3-carbinol (I3C). These pesticides significantly increase the ratio of 16 alpha-OHE1/2-OHE1 metabolites to values comparable to or greater than those observed after DMBA. In contrast, the antitumor agent I3C increased 2-OHE1 formation and yielded ratios that are 1/3 of those found in unexposed control cells and 1/10th of those found in DMBA-treated cells. Thus the ratio of 16 alpha-OHE1/2-OHE1 may provide a marker for the risk of breast cancer. Assays of this ratio, which can be measured in spot urines, may prove useful for a variety of in vitro and in vivo studies bearing on breast cancer risk.
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PMID:Effects of pesticides on the ratio of 16 alpha/2-hydroxyestrone: a biologic marker of breast cancer risk. 859 62


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