Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0006142 (breast cancer)
 160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

3,3'-Diindolylmethane (DIM) is a major in vivo derivative of the putative anticancer agent indole-3-carbinol (I3C), which is present in vegetables of the Brassica genus. At concentrations above 10 microM, DIM inhibited DNA synthesis and cell proliferation in both estrogen receptor replete (MCF-7) and deficient (MDA-MB-231) human breast cancer cells in a concentration- and time-dependent manner. These antiproliferative effects were accompanied by characteristic indications of programmed cell death in both cell lines, including externalization of phosphatidylserine, chromatin condensation, and DNA fragmentation. Furthermore, Western and Northern blot analyses, as well as coimmunoprecipitation assays, revealed that in both MCF-7 and MDA-MB-231 cells, DIM treatment decreased total transcript and protein levels of the apoptosis inhibitory protein Bcl-2, and the amount of Bcl-2 bound to the pro-apoptotic protein Bax. DIM treatment also caused an increase in Bax protein levels, but did not affect the level of Bax that was bound to Bcl-2. As a functional test of the role of Bcl-2 down-regulation in the DIM-induced apoptotic response, ectopic expression of Bcl-2 in MCF-7 cells was shown to attenuate the apoptotic effect of DIM. These results demonstrate that DIM can induce apoptosis in breast cancer cells independent of estrogen receptor status by a process that is mediated by the modulated expression of the Bax/Bcl-2 family of apoptotic regulatory factors.
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PMID:Bcl-2 family-mediated apoptotic effects of 3,3'-diindolylmethane (DIM) in human breast cancer cells. 1193 41

The use of naturally occurring phytoantiestrogens for prevention and therapy of breast cancer is an alternative to synthetic antiestrogens. We have been examining the mechanism of action of the antiestrogen indole-3-carbinol (I3C), a constituent of compounds present in cruciferous vegetables. I3C abrogates the cell-proliferative effect of 17 beta-estradiol (E2), as observed in several different estradiol-responsive breast cancer cell lines and isolated cell clones. Modulation of E2 activity by I3C, in part, was by the induction of the 2-hydroxylation pathway, one of the two competing hydroxylation pathways of estrone conversion that resulted in the formation of metabolites with antiestrogenic properties. I3C-mediated induction of the 2-hydroxylation pathway correlated with a selective induction of cytochrome P-450 1A1 by I3C in E2-responsive human breast cancer cells. Induction of neither the 2-hydroxylation pathway nor cytochrome P-450 1A1 was observed in estrogen-nonresponsive human breast cancer cells. This selective effect warranted a further search for biochemical targets of I3C related to E2 function. To this end, we observed that E2-mediated phosphorylation of the estrogen receptor is inhibited by I3C. Our results are consistent with the hypothesis that I3C exerts its antiestrogenic effect by intervention in the E2-estrogen receptor signal transduction pathways and by alterations in E2 metabolism that resulted in the formation of metabolites with antiestrogenic activity.
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PMID:Abrogation of estrogen-mediated cellular and biochemical effects by indole-3-carbinol. 1209 23

Indole-3-carbinol (I3C) or, more correctly, its acid condensation products act as chemoprotective agents via several mechanisms. It induces the expression of cytochrome P-450 1A1, which shifts the estrogen metabolic pathway in favor of C-2 hydroxylation and away from the formation of 16 alpha-hydroxyestrone, a suspected endogenous carcinogen. Increased 16 alpha-hydroxylation of estrogen is associated with greater risk of cancer of the cervix, breast, endometrium, and larynx. The production of 4-hydroxyestrone is also inhibited by I3C. I3C can induce a G1 cell cycle arrest in human MCF-7 breast cancer cells. It can suppress aberrant crypt foci. I3C significantly inhibits the cell adhesion, spreading, and invasion associated with an upregulation of PTEN (a tumor suppressor gene) and E-cadherin (a regulator of cell-cell adhesion) expression in T47-D human breast cancer cells. Thus I3C exhibits anticancer activities by suppressing breast tumor cell growth and metastatic spread. A gas chromatography-mass spectrometry method for the quantitation of diindolylmethane, the principal acid condensation product of I3C, has been developed for use in determining compliance in subjects who have been treated with I3C. The method utilizes a 1-ml urine sample. We have used this method to correlate I3C ingestion with regression of cervical intraepithelial neoplasia in a population of women at risk for cervical cancer. The assay provides an objective marker of consumption using a noninvasive biological fluid and illustrates that diindolylmethane may be used as a marker of compliance in I3C dietary intervention studies.
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PMID:Quantitative determination of 3,3'-diindolylmethane in urine of individuals receiving indole-3-carbinol. 1209 29

The mechanism of action of the anti-estrogen indole-3-carbinol (I3C), present in cruciferous vegetables, is being examined in our laboratory with a view to promote the use of this naturally occurring chemopreventive as an alternative to synthetic anti-estrogens in human breast cancer. Our previous results clearly demonstrated that despite its low affinity for the estrogen receptor (ER), I3C abrogated estradiol-mediated cellular and biochemical effects in estradiol-responsive cells and tissues. In an earlier report, we identified ER phosphorylation as one of the targets of I3C, and in this communication we describe the consequence of inhibition of ER phosphorylation. Estradiol-induced DNA-binding proteins that bound to several DNA-responsive elements were inhibited by I3C and this effect was not at the level of DNA-protein physical interaction as inclusion of I3C in vitro in the reaction mix did not affect the binding. We analyzed the spectrum of genes induced by estradiol and modulated and/or intercepted by I3C. Our results conclude that although estradiol-mediated functions are affected by I3C, its biochemical targets are multiple and some of these may be modulated by the oligomeric products of I3C.
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PMID:Multiple molecular targets of indole-3-carbinol, a chemopreventive anti-estrogen in breast cancer. 1257 Mar 40

Cruciferous vegetables contain glucobrassicin which, during metabolism, yields indole-3-carbinol (I3C). In a low pH environment I3C is converted into polymeric products, among which 3,3'-diindolylmethane (DIM) is the main one. The apoptotic effects of I3C and DIM were exhibited in human breast cancer cells. The objectives of this study were: (a) examination of the potential effects of I3C and DIM on the proliferation and induction of apoptosis in human prostate cancer cell lines with different p53 status; (b) to try to characterise the mechanism(s) involved in these effects. Our results indicate that both indole derivatives suppress the growth of these cells in a dose- and time-dependent manner, by inducing apoptosis. It appears that these indolic compounds may offer effective means against prostate cancer. Induction of apoptosis was p53-independent. Moreover, the indole derivatives employed did not affect the levels of bcl-2, bax and fasL.
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PMID:Indole-3-carbinol and 3,3'-diindolylmethane induce apoptosis in human prostate cancer cells. 1273 79

Recent results from epidemiology, in vitro cell culture and in vivo (animal and human) studies have suggested the benefits of indole-3-carbinol (I3C) for the prevention of many types of cancer, including breast cancer. However, there are no reports, to the best of our knowledge, on the effect of I3C on isogenic nontumorigenic and tumorigenic breast epithelial cells, and there is a significant void in our understanding of the molecular mechanism(s) by which I3C induces apoptotic cell death in breast cancer cells. To fill this gap in our understanding, we conducted experiments to investigate the effects of I3C on an isogenic nontumorigenic (MCF10A) and tumorigenic (MCF10CA1a [CA1a]) breast epithelial cells. Here we show that CA1a cells are more sensitive to low concentration of I3C in terms of cell growth inhibition compared to MCF10A cells. We further report that I3C upregulates Bax/Bcl-2 ratio and downregulates Bcl-xL expression in CA1a cells but not in MCF10A cells. We also report, for the first time, that I3C induces Bax translocation to the mitochondria, causing mitochondrial depolarization, resulting in the loss of mitochondrial potential leading to the release of cytochrome c and subsequent cell death in CA1a cells but not in MCF10A cells. From these results, we conclude that I3C selectively induces apoptosis in breast cancer cells, but not in nontumorigenic breast epithelial cells, suggesting the potential therapeutic benefit of I3C against breast cancer.
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PMID:Indole-3-carbinol (I3C) induces apoptosis in tumorigenic but not in nontumorigenic breast epithelial cells. 1279 10

Indole-3-carbinol (I3C), a natural component of Brassica vegetables, has been found to be a promising cancer preventive agent. However, the precise molecular mechanism(s) by which I3C exerts its inhibitory effects on cancer cells has not been fully elucidated. We investigated the molecular mechanism of action of I3C during apoptotic processes in breast epithelial cells. Nontumorigenic and tumorigenic breast epithelial cells were exposed to I3C, and growth inhibition, apoptosis and expression of genes involved in apoptotic processes were measured. Translocation of Bax to the mitochondria was accessed by confocal imaging. Mitochondrial potential and cytochrome c release also were measured. We found that I3C inhibited the growth of breast cancer cells and induced apoptosis in these cells, concomitant with upregulation of Bax, and downregulation of Bcl-2. I3C induced translocation of Bax to the mitochondria in both tumorigenic and nontumorigenic cells, but concomitant loss of mitochondrial potential, release of cytochrome c and induction of apoptosis were observed only in cancer cells. In conclusion, I3C exerts its effects by regulating cell cycle and by altering the expression of genes involved in apoptotic pathway. The translocation of Bax to the mitochondria alone is not sufficient during I3C-induced apoptosis. Translocation of Bax followed by mitochondrial depolarization and cytochrome c release is necessary, which may be responsible for selective induction of apoptosis in cancer cells, supporting the potential preventive and/or therapeutic benefit of I3C against cancers.
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PMID:Bax translocation to mitochondria is an important event in inducing apoptotic cell death by indole-3-carbinol (I3C) treatment of breast cancer cells. 1284 Feb 20

Indole-3-carbinol (I3C), a compound that occurs naturally in Brassica vegetables such as cabbage and broccoli, can induce a G1 cell-cycle arrest of human MCF-7 breast cancer cells that is accompanied by the selective inhibition of cyclin-dependent kinase 6 (Cdk6) expression and stimulation of p21(Waf1/Cip1) gene expression. Construction and transfection of a series of promoter-reporter plasmids demonstrate that the indole-regulated changes in Cdk6 and p21(Waf1/Cip1) levels are due to specific effects on their corresponding promoters. Mutagenic analysis reveals that I3C signaling targets a composite transcriptional element in the Cdk6 promoter that requires both Sp1 and Ets transcription factors for transactivation function. Analysis of protein-DNA complexes formed with nuclear proteins isolated from I3C-treated and -untreated cells demonstrates that the Sp1 DNA element in the Cdk6 promoter interacts with an I3C-inhibited protein-protein complex that contains the Sp1 transcription factor. In indole-treated cells, a fraction of [(3)H]I3C was converted into its natural diindole product (3)H-labeled 3-3'-diindolylmethane ([(3)H]DIM), which accumulates in the nucleus; this suggests that DIM may have a role in the transcriptional activities of I3C. Mutagenic analysis of the p21(Waf1/Cip1) promoter reveals that in transfected breast cancer cells, DIM (as well as I3C) stimulates p21(Waf1/Cip1) transcription through an indole-responsive region of the promoter that contains multiple Sp1 consensus sequences. Furthermore, DIM treatment regulates the presence of a nuclear Sp1 DNA-binding activity. Our results demonstrate that both the Cdk6 and p21(Waf1/Cip1) promoters are newly defined downstream targets of the indole-signaling pathway, and that the observed transcriptional effects are due to a combination of the cellular activities of I3C and DIM.
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PMID:Indole-3-carbinol and 3-3'-diindolylmethane antiproliferative signaling pathways control cell-cycle gene transcription in human breast cancer cells by regulating promoter-Sp1 transcription factor interactions. 1284 Feb 23

Studies increasingly indicate that dietary indole-3-carbinol (I3C) prevents the development of estrogen-enhanced cancers including breast, endometrial and cervical cancers. Epidemiological, laboratory, animal and translational studies support the efficacy of I3C. Whereas estrogen increases the growth and survival of tumors, I3C causes growth arrest and increased apoptosis and ameliorates the effects of estrogen. Our long-range goal is to best use I3C together with other nutrients to achieve maximum benefits for cancer prevention. This study examines the possibility that induction of growth arrest in response to DNA damage (GADD) in genes by diindolylmethane (DIM), which is the acid-catalyzed condensation product of I3C, promotes metabolically stressed cancer cells to undergo apoptosis. We evaluated whether genistein, which is the major isoflavonoid in soy, would alter the ability of I3C/DIM to cause apoptosis and decrease expression driven by the estrogen receptor (ER)-alpha. Expression of GADD was evaluated by real-time reverse transcription-polymerase chain reaction. Proliferation and apoptosis were measured by a mitochondrial function assay and by fluorescence-activated cell sorting analysis. The luciferase reporter assay was used to specifically evaluate expression driven by ER-alpha. The estrogen-sensitive MCF-7 breast cancer cell line was used for these studies. We show a synergistic effect of I3C and genistein for induction of GADD expression, thus increasing apoptosis, and for decrease of expression driven by ER-alpha. Because of the synergistic effect of I3C and genistein, the potential exists for prophylactic or therapeutic efficacy of lower concentrations of each phytochemical when used in combination.
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PMID:Indole-3-carbinol is a negative regulator of estrogen. 1284 Feb 26

Indole-3-carbinol (I3C), autolysis product of glucosinolates present in cruciferous vegetables, has been indicated as a promising agent in preventing the development and progression of breast cancer. I3C has been shown to inhibit the growth of human cancer cells in vitro and possesses anticarcinogenic activity in vivo. Because I3C is unstable and may be converted into many polymeric products in the digestive tract, it is not yet clear whether the biological activity observed can be attributed to I3C or some of its polymeric products. In this study we synthesized a stable I3C cyclic tetrameric derivative and investigated its effects on a panel of human breast cancer cell lines. The I3C tetramer suppressed the growth of both estrogen receptor (ER) -positive (MCF-7, 734B, and BT474) and ER-negative (BT20, MDA-MB-231, and BT539) human breast cancer cell lines, and it was found to induce G(1) cell cycle arrest in a dose-dependent manner without evidence of apoptosis, suggesting a growth arrest via a cytostatic mechanism. At the molecular level, the tetramer inhibited cyclin-dependent kinase (CDK) 6 expression and activity, induced an increase in the level of p27(kip1), and reduced the level of retinoblastoma protein expression. Contrarily to CDK6, the level of CDK4, the other kinase involved in the G(1) phase of the cell cycle, remains unchanged. Interestingly, the tetramer resulted about five times more active than I3C in suppressing the growth of human breast cancer cells. On the whole, our data suggest that the I3C tetrameric derivative is a novel lead inhibitor of breast cancer cell growth that may be a considered a new, promising therapeutic agent for both ER+ and ER- breast cancer.
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PMID:A new indole-3-carbinol tetrameric derivative inhibits cyclin-dependent kinase 6 expression, and induces G1 cell cycle arrest in both estrogen-dependent and estrogen-independent breast cancer cell lines. 1287 2


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