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)

It has been reported that Breast Cancer Susceptibility gene-1 & 2 (BRCA1 & 2 are potential molecular targets for chemoprevention by isoflavone genistein (4' 5, 7-trihydroxy isoflavone), in breast and prostate cancer cells. It is also known that BRCA1 has inhibitory activity on estrogen receptor-alpha and genistein's action on cells is mainly through modulation of estrogen receptor activity. The action of genistein with respect to BRCA1 status in ovarian cancer cells has not been reported so far. Therefore in this study, we analyzed the action of genistein on BRCA1 antisense blocked (AS4) and unblocked (NEO) BG-1 ovarian cancer cells. We found that genistein induced comparable cytotoxic effect in both AS4 and NEO cells, but through different pathways. We found that genistein induces caspase 8 dependent apoptotic pathway in NEO cells. Genistein inhibits estrogen receptor-alpha and activates BARD1 in BRCA1 blocked cells and induces estrogen receptor-beta and FAS in presence of BRCA1. It can be concluded that even though there is no difference in the extent of cell death or apoptosis, the molecular mechanism of action of genistein in inducing apoptosis is different in BRCA1 blocked and unblocked cells. This could partially explain the beneficial effects of genistein in both wild type and mutated BRCA1 estrogen receptor positive tumors.
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PMID:Genistein induces apoptosis in ovarian cancer cells via different molecular pathways depending on Breast Cancer Susceptibility gene-1 (BRCA1) status. 1851 88

AMAD, an emodin azide methyl anthraquinone derivative, was extracted from the nature giant knotweed rhizome of traditional Chinese herbs. Here, we investigated the anticancer activities and signaling pathways implicated in AMAD-induced apoptosis in human breast cancer cell lines MDA-MB-453 and human lung adenocarcinoma Calu-3 cells. AMAD was found to have a potent cytotoxic effect on both cell lines. Hoechst 33258 staining and Annexin V/propidium iodide double staining exhibited the typical nuclear features of apoptosis and increased the proportion of apoptotic Annexin V-positive cells in a dose-dependent manner, respectively. Moreover, this apoptotic induction was associated with a collapse of the mitochondrial membrane potential and activated caspases (cysteine aspartase) cascade involving in caspase-8, caspase-9, caspase-3, and poly(ADP-ribose) polymerase cleavage in a concentration-dependent manner. It was noteworthy that AMAD also effectively cleaved Bid, a BH3 domain-containing proapoptotic Bcl-2 family member, and induced the subsequent release of cytochrome c from mitochondria into the cytosol. Furthermore, suppression of caspase-8 activity with Z-IETD-FMK partially inhibited release of cytochrome c and Bid cleavage induced by AMAD, whereas exposure to Z-LETD-FMK, a caspase-9 inhibitor, had no effect. Additionally, there was significant change in other mitochondrial membrane proteins triggered by AMAD, such as Bcl-xl and Bad. It was intriguing that AMAD decreased the generation of reactive oxygen species in both cell lines. DNA-binding assay exhibited apoptosis induced by AMAD was not involved in intercalating to DNA. Taken together, these data suggested that AMAD induced apoptosis via a mitochondrial pathway involving caspase-8/Bid activation in both cell lines.
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PMID:Emodin azide methyl anthraquinone derivative triggers mitochondrial-dependent cell apoptosis involving in caspase-8-mediated Bid cleavage. 1856 40

In recent years, studies with plant compounds have shown both chemotherapeutic and chemopreventive properties. This study with plant stress hormones (jasmonates) showed growth inhibitory effects in breast cancer cells. cis-Jasmone and methyl jasmonate (MJ) inhibited the long-term proliferation of MDA-MB-435 and MCF-7 cells. Cell cycle analysis showed G0/G1 and S-phase arrest with increasing apoptotic population. Cellular signaling studies with MJ showed decreased membrane fluidity and activation of extrinsic and intrinsic apoptotic pathways. Specifically in extrinsic apoptotic pathway increased expression of TNF receptor 1, activation of mitogen-activated protein kinase and caspase-8 was observed. MJ also decreased the mitochondrial membrane potential and activated caspase-3 in breast cancer cells. In conclusion our results revealed novel-signaling mechanism of MJ in breast cancer cells, indicating that MJ could have potential applications for chemotherapeutic purposes.
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PMID:Methyl jasmonate decreases membrane fluidity and induces apoptosis through tumor necrosis factor receptor 1 in breast cancer cells. 1869 87

Tamoxifen has efficacy as a breast cancer therapy and chemoprevention agent. However, toxicity and resistance to tamoxifen limit its clinical application. There is an urgent need to develop compounds that may be combined with tamoxifen to improve efficacy and overcome toxicity and resistance. We showed previously that the organoselenium compound methylseleninic acid (MSA) increased the growth-inhibitory effect of tamoxifen and reversed tamoxifen resistance in breast cancer cells. In this study, we examined the mechanism for induction of apoptosis by MSA combined with tamoxifen in tamoxifen-sensitive and tamoxifen-resistant breast cancer cells. 4-hydroxytamoxifen (TAM; 10(-7) mol/L) alone resulted in cell cycle arrest but no apoptosis, whereas MSA alone (10 micromol/L) induced apoptosis in tamoxifen-sensitive cells. Combination of MSA with TAM resulted in a synergistic apoptosis in both tamoxifen-sensitive and tamoxifen-resistant breast cancer cells compared with either agent alone. MSA and MSA combined with TAM induced apoptosis through the intrinsic, mitochondrial apoptotic pathway. MSA induced a sequential activation of caspase-9 and then caspase-8. These results indicate that the growth inhibition synergy and reversal of tamoxifen resistance by combination of selenium with tamoxifen occurs via a tamoxifen-induced cell cycle arrest, allowing more cells to enter the intrinsic apoptotic pathway elicited by selenium.
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PMID:Methylseleninic acid synergizes with tamoxifen to induce caspase-mediated apoptosis in breast cancer cells. 1879 Jul 85

Cellular-FLICE inhibitory protein (c-FLIP) is an inhibitor of apoptosis downstream of the death receptors Fas, DR4, and DR5, and is expressed as long (c-FLIP(L)) and short (c-FLIP(S)) splice forms. We found that the knockdown of c-FLIP using small interfering RNA (siRNA) triggered ligand-independent caspase-8- and -9-dependent spontaneous apoptosis and decreased the proliferation of MCF-7 breast cancer cells. Further analysis revealed that an apoptotic inhibitory complex (AIC) comprised of DR5, FADD, caspase-8, and c-FLIP(L) exists in MCF-7 cells, and the absence of c-FLIP(L) from this complex induces DR5- and FADD-mediated caspase-8 activation in the death inducing signaling complex (DISC). c-FLIP(S) was not detected in the AIC, and using splice form-specific siRNAs we showed that c-FLIP(L) but not c-FLIP(S) is required to prevent spontaneous death signaling in MCF-7 cells. These results clearly show that c-FLIP(L) prevents ligand-independent death signaling and provides direct support for studying c-FLIP as a relevant therapeutic target for breast cancers.
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PMID:c-FLIP knockdown induces ligand-independent DR5-, FADD-, caspase-8-, and caspase-9-dependent apoptosis in breast cancer cells. 1884 Apr 11

This study investigated the role of the caspase activation cascade in extrinsic and intrinsic apoptosis induced by equol in human breast cancer MDA-MB cells. First, the antiproliferative effect of equol was determined in cells treated with 1-100 microM equol for 24, 48, and 72h. Equol significantly inhibited cell proliferation in a dose-dependent manner (p<0.05). Exposure to 50 or 100 microM equol for 72h strongly promoted apoptosis. Under the same conditions, remarkable cytochrome c release was observed. Subsequently, caspase-9, which acts in mitochondria-mediated apoptosis, was cleaved by equol at high concentrations, but caspase-8 activation of receptor-mediated apoptosis was not observed. At both equol concentrations, the caspase-8 and -9 activity assays showed similar patterns. In addition, equol treatment activated caspase-3, which is downstream from caspase-9, and this was accompanied by the cleavage of capase-6 and -7. Activation of these caspases leads to increased activation of PARP, lamin, and ICAD. This study suggests that equol induces the intrinsic pathway of apoptosis via caspase-9 and cytochrome c, independent of caspase-8, in human breast cancer MDA-MB-453 cells.
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PMID:Equol induces apoptosis through cytochrome c-mediated caspases cascade in human breast cancer MDA-MB-453 cells. 1897 49

Xanthorrhizol is a natural sesquiterpenoid compound isolated from the rhizome of Curcuma xanthorrhizza Roxb (Zingerberaceae). Recent studies of xanthorrhizol in cell cultures strongly support the role of xanthorrhizol as an antiproliferative agent. In our study, we tested the antiproliferative effect of xanthorrhizol using different breast cancer cell lines. The invasive breast cancer cell line, MDA-MB-231, was then selected for further investigations. Treatment with xanthorrhizol caused 50% growth inhibition on MDA-MB-231 cells at 8.67 +/- 0.79 microg/ml as determined by sulforhodamine B (SRB) assay. Hoechst 33258 nuclear staining assay showed the rate of apoptosis of MDA-MB-231 cells to increase in response to xanthorrhizol treatment. Immunofluorescence staining using antibody MitoCapture and fluorescein isothiocyanate (FITC)-labeled cytochrome c revealed the possibility of altered mitochondrial transmembrane potential and the release of cytochrome c respectively. This was further confirmed by Western-blotting, where cytochrome c was showed to migrate from mitochondrial fraction to the cytosol fraction of treated MDA-MB-231 cells. Caspase activity assay showed the involvement of caspase-3 and caspase-9, but not caspase-6 or caspase-8 in MDA-MB-231 apoptotic cell death. Subsequently, cleavage of PARP-1 protein is suggested. These data suggest treatment with xanthorrhizol modulates MDA-MB-231 cell apoptosis through the mitochondria-mediated pathway subsequent to the disruption of mitochondrial transmembrane potential, release of cytochrome c, activation of caspase-3 and caspase-9, and the modulation of PARP-1 protein.
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PMID:Antiproliferative property and apoptotic effect of xanthorrhizol on MDA-MB-231 breast cancer cells. 1918 49

Ductal carcinoma in situ (DCIS) is characterized by ductal epithelial cells that have filled the luminal space of the breast duct and survive despite loss of extracellular matrix contact. In normal epithelial cells, the loss of such contact triggers a form of apoptosis known as detachment-induced apoptosis or "anoikis." TMS1/ASC is a bipartite adaptor molecule that participates in inflammatory and apoptotic signaling pathways. Epigenetic silencing of TMS1 has been observed in a significant proportion of human breast and other cancers, but the mechanism by which TMS1 silencing contributes to carcinogenesis is unknown. Here, we examined the role of TMS1 in anoikis. We found that TMS1 expression is induced in response to loss of substratum interactions in breast epithelial cells. siRNA-mediated knockdown of TMS1 leads to anoikis resistance, due in part to the persistent activation of extracellular signal-regulated kinase and an impaired ability to up-regulate the BH3-only protein Bim. We further show that the detachment-induced cleavage of procaspase-8, a newly described mediator of cellular adhesion, is significantly inhibited in the absence of TMS1. These data show a novel upstream role for TMS1 in the promotion of anoikis, and suggest that silencing of TMS1 may contribute to the pathogenesis of breast cancer by allowing epithelial cells to bypass cell death in the early stages of breast cancer development. This conclusion is supported by in vivo data showing that TMS1 is selectively down-regulated in the aberrant epithelial cells filling the lumen of the breast duct in a subset of primary DCIS lesions.
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PMID:Silencing of TMS1/ASC promotes resistance to anoikis in breast epithelial cells. 1922 47

Recent large-scale studies have been successful in identifying common, low-penetrance variants associated with common cancers. One such variant in the caspase-8 (CASP8) gene, D302H (rs1045485), has been confirmed to be associated with breast cancer risk, although the functional effect of this polymorphism (if any) is not yet clear. In order to further map the CASP8 gene with respect to breast cancer susceptibility, we performed extensive haplotype analyses using single nucleotide polymorphisms (SNP) chosen to tag all common variations in the gene (tSNP). We used a staged study design based on 3,200 breast cancer and 3,324 control subjects from the United Kingdom, Utah, and Germany. Using a haplotype-mining algorithm in the UK cohort, we identified a four-SNP haplotype that was significantly associated with breast cancer and that was superior to any other single or multi-locus combination (P=8.0 x 10(-5)), with a per allele odds ratio and 95% confidence interval of 1.30 (1.12-1.49). The result remained significant after adjustment for the multiple testing inherent in mining techniques (false discovery rate, q=0.044). As expected, this haplotype includes the D302H locus. Multicenter analyses on a subset of the tSNPs yielded consistent results. This risk haplotype is likely to carry one or more underlying breast cancer susceptibility alleles, making it an excellent candidate for resequencing in homozygous individuals. An understanding of the mode of action of these alleles will aid risk assessment and may lead to the identification of novel treatment targets in breast cancer.
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PMID:A breast cancer risk haplotype in the caspase-8 gene. 1931 53

Malignant melanomas are generally drug resistant and have a very poor prognosis. We have studied the effects of a chemical conjugate of pseudomonas exotoxin A (PE) and the antibody 9.2.27, which recognizes the high molecular weight melanoma associated antigen (HMW-MAA) expressed in most malignant melanomas and melanoma cell lines. We demonstrate that the 9.2.27PE immunotoxin (IT) induces cell death in malignant melanoma cells through protein synthesis inhibition followed by some morphological and biochemical features of apoptosis, like rounding up of cells, chromatin condensation and inactivation of PARP. Unlike previous results with the 425.3PE IT in breast cancer cells, we detected no depolarization of the mitochondrial membrane after 9.2.27PE IT treatment. This is likely due to the lack of strong activation of caspase-8 and caspase-3. The lack of depolarization suggests that cytochrome c, a molecule that triggers activation of caspase-3, was retained within the mitochondria. In addition, the protein level of the antiapoptotic Bcl-2 did not decrease in contrast to other antiapoptotic molecules belonging to the inhibitor of apoptosis and the Bcl-2 family. This suggests that Bcl-2 may play a role in maintaining the mitochondrial membrane integrity in the 9.2.27PE-treated cells. Nevertheless, 9.2.27PE IT efficiently killed malignant melanoma cells that can be ascribed to inhibition of protein synthesis followed by some morphological and biochemical features of apoptosis.
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PMID:The melanoma specific 9.2.27PE immunotoxin efficiently kills melanoma cells in vitro. 1935 Jun 33


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