Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Food components influence the physiology by modulating gene expression and biochemical pathways within the human body. The disease-preventive roles of several fruit and vegetable components have been related to such properties. Polyphenolic components such as flavonoids are strong antioxidants and induce the expression of several xenobiotic-detoxifying enzymes. The mechanism of selective cytotoxicity induced by red grape wine polyphenols against MCF-7 breast cancer cells was investigated in relation to their interference with calcium homeostasis. MCF-7 cells showed an increase in cytosolic calcium levels within 10 min of treatment with the polyphenols. Immunohistochemical localization of calmodulin with secondary gold-labeled antibodies showed similar levels of gold labeling in both MCF-7 cells and the spontaneously immortalized, normal MCF-10A cell line. MCF-7 cells treated with the red wine polyphenol fraction (RWPF) showed swelling of endoplasmic reticulum, dissolution of the nucleus, and loss of plasma membrane integrity as well as reduced mitochondrial membrane potential. These cells were arrested at the G2/M interphase. By contrast, MCF-10A cells did not show such changes after RWPF treatment. The results suggest that polyphenol-induced calcium release may disrupt mitochondrial function and cause membrane damage, resulting in selective cytotoxicity toward MCF-7 cells. This property could further be developed toward breast cancer prevention strategies either independently or in conjunction with conventional prevention therapies where a positive drug-nutrient interaction can be demonstrated.
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PMID:Treatment of mcf-7 breast cancer cells with a red grape wine polyphenol fraction results in disruption of calcium homeostasis and cell cycle arrest causing selective cytotoxicity. 1700 70

Flavonoids, polyphenolic phytochemicals which include flavones and isoflavones, are present in the common human diet. It has been suggested that these compounds may exert anticancer activity; however, the mechanisms involved remain unknown. We have recently shown (Sergeev, 2004, Biochem Biophys Res Commun 321: 462-467) that isoflavones can activate the novel apoptotic pathway mediated by cellular Ca(2+). Here, we report that polymethoxyflavones (PMFs) derived from sweet orange (Citrus sinensis L.) inhibit growth of human breast cancer cells via Ca(2+)-dependent apoptotic mechanism. The treatment of MCF-7 breast cancer cells with 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-OH-HxMF) and 3'-hydroxy-5,6,7,4'-tetramethoxyflavone (3'-OH-TtMF) induced a sustained increase in concentration of intracellular Ca(2+) ([Ca(2+)](i)) resulting from both depletion of the endoplasmic reticulum Ca(2+) stores and Ca(2+) influx from the extracellular space. This increase in [Ca(2+)](i) was associated with the activation of the Ca(2+)-dependent apoptotic proteases, mu-calpain and caspase-12, as evaluated with the calpain and caspase-12 peptide substrates and antibodies to active (cleaved) forms of the enzymes. Corresponding non-hydroxylated PMFs, 3,5,6,7,8,3',4'-heptamethoxyflavone (HpMF) and 5,6,7,3',4'-pentamethoxyflavone (PtMF), were dramatically less active in inducing Ca(2+)-mediated apoptosis. Our results strongly suggest that the cellular Ca(2+) modulating activity of flavonoids underlies their apoptotic mechanism and that hydroxylation of PMFs is critical for their ability to induce an increase in [Ca(2+)](i) and, thus, activate Ca(2+)-dependent apoptotic proteases.
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PMID:Polymethoxylated flavones induce Ca(2+)-mediated apoptosis in breast cancer cells. 1704 27

Caveolin-1 (CAV1), a highly conserved membrane-associated protein, is a putative regulator of cellular transformation. CAV1 is localized in the plasmalemma, secretory vesicles, Golgi, mitochondria, and endoplasmic reticulum membrane and associates with the microtubule cytoskeleton. Taxanes such as paclitaxel (Taxol) are potent anti-tumor agents that repress the dynamic instability of microtubules and arrest cells in the G(2)/M phase. Src phosphorylation of Tyr-14 on CAV1 regulates its cellular localization and function. We report that phosphorylation of CAV1 on Tyr-14 regulates paclitaxel-mediated apoptosis in MCF-7 breast cancer cells. Befitting its role as a multitasking molecule, we show that CAV1 sensitizes cells to apoptosis by regulating cell cycle progression and activation of the apoptotic signaling molecules BCL2, p53, and p21. We demonstrate that phosphorylated CAV1 triggers apoptosis by inactivating BCL2 and increasing mitochondrial permeability more efficiently than non-phosphorylated CAV1. Furthermore, expression of p21, which correlates with taxane sensitivity, is regulated by CAV1 phosphorylation in a p53-dependent manner. Collectively, our findings underscore the importance of CAV1 phosphorylation in apoptosis and suggest that events that negate CAV1 tyrosine phosphorylation may contribute to anti-microtubule drug resistance.
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PMID:Caveolin-1 tyrosine phosphorylation enhances paclitaxel-mediated cytotoxicity. 1719 Aug 31

Earlier studies suggested that TSP50 is a testis-specific gene that encodes a protein, which is homologous to serine proteases but differs in that threonine replaces serine in its catalytic triad. Most importantly, it was abnormally reactivated in many breast cancer biopsies tested. While further investigating its biochemical and cell biological natures, we found that TSP50 exhibited enzyme activity and was located in the endoplasmic reticulum and cytosol membrane. During our studies to elucidate the regulatory mechanisms related to its differential expression, we discovered a putative p53-binding site and several Sp1-binding sites in the TSP50 promoter, which led us to test if it was regulated by the p53 gene. We found that the p53 transgene negatively regulated the TSP50 promoter in diverse types of cell lines. This result was consistent with other observations: (a) p53 overexpression reduced endogenous TSP50 expression; and (b) breast cancer cell lines containing mutated p53, such as MCF7/Adr, or normal p53, such as MCF7, produced high or low levels of TSP50 transcripts, which was consistent with the fact that TSP50 promoter activity was much higher in MCF7/Adr than that in MCF7 cells. We also found that the quantity of Sp1 transcription factor was lower in MCF7/Adr than in MCF7 cells, which suggested that another mechanism (i.e., transcription factor modulation) was also involved in TSP50 differential expression.
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PMID:TSP50 encodes a testis-specific protease and is negatively regulated by p53. 1728 60

The present work investigates the relationship between cancer cell chemosensitivity and subcellular distribution, molecular interaction, and metabolism of an anticancer drug. To get insights into this relationship, we took advantage of the differential sensitivity of two breast cancer cell lines, MDA-MB-231 and MCF-7, to anthracyclines, along with the property of docosahexaenoic acid (DHA, 22:6n-3), to differentially enhance their cytotoxic activity. The fluorescent drug mitoxantrone (MTX) was used because of the possibility to study its subcellular accumulation by confocal spectral imaging (CSI). The use of CSI allowed us to obtain semiquantitative maps of four intracellular species: nuclear MTX bound to DNA, MTX oxidative metabolite in endoplasmic reticulum, cytosolic MTX, and finally, MTX in a low polarity environment characteristic of membranes. MDA-MB-231 cells were found to be more sensitive to MTX (IC50 = 18 nM) than MCF-7 cells (IC50 = 196 nM). According to fluorescence levels, the nuclear and cytosolic MTX content was higher in MCF-7 than in MDA-MB-231 cells, indicating that mechanisms other than nuclear MTX accumulation account for chemosensitivity. In the cytosol, the relative proportion of oxidized MTX was higher in MDA-MB-231 (60%) than in MCF-7 (7%) cells. DHA sensitized MDA-MB-231 (approximately 4-fold) but not MCF-7 cells to MTX and increased MTX accumulation by 1.5-fold in MDA-MB-231 cells only. The DHA-stimulated accumulation of MTX was attributed mainly to the oxidative metabolite. Antioxidant N-acetyl-L-cysteine inhibited the DHA effect on both metabolite accumulation and cell sensitization to MTX. We conclude that drug metabolism and compartmentalization are associated with cell chemosensitization, and the related cytotoxicity mechanisms may involve oxidative stress.
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PMID:Differential subcellular distribution of mitoxantrone in relation to chemosensitization in two human breast cancer cell lines. 1729 24

The recent development of hormonal therapy that blocks estrogen synthesis represents a major advance in the treatment of estrogen receptor-positive breast cancer. However, cancer cells often acquire adaptations resulting in resistance. A recent report reveals that estrogen starvation-induced apoptosis of breast cancer cells requires BIK, an apoptotic BH3-only protein located primarily at the endoplasmic reticulum (ER). Searching for novel partners that interact with BIK at the ER, we discovered that BIK selectively forms complex with the glucose-regulated protein GRP78/BiP, a major ER chaperone with prosurvival properties naturally induced in the tumor microenvironment. GRP78 overexpression decreases apoptosis of 293T cells induced by ER-targeted BIK. For estrogen-dependent MCF-7/BUS breast cancer cells, overexpression of GRP78 inhibits estrogen starvation-induced BAX activation, mitochondrial permeability transition, and consequent apoptosis. Further, knockdown of endogenous GRP78 by small interfering RNA (siRNA) sensitizes MCF-7/BUS cells to estrogen starvation-induced apoptosis. This effect was substantially reduced when the expression of BIK was also reduced by siRNA. Our results provide the first evidence that GRP78 confers resistance to estrogen starvation-induced apoptosis in human breast cancer cells via a novel mechanism mediated by BIK. These results further suggest that GRP78 expression level in the tumor cells may serve as a prognostic marker for responsiveness to hormonal therapy based on estrogen starvation and that combination therapy targeting GRP78 may enhance efficacy and reduce resistance.
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PMID:GRP78/BiP inhibits endoplasmic reticulum BIK and protects human breast cancer cells against estrogen starvation-induced apoptosis. 1744 86

Breast tissue possesses the enzymes for local estrogen biosynthesis. We measured the effect of Estradiol (E2), Tibolone (OrgOD14) and its metabolite Org4094 on estrone sulfate (E1S)-sulfatase (STS) using breast cancer (MCF-7) and non-malignant breast cells (HBL-100). Cells were cultured in 5% steroid depleted fetal calf serum for 3 days and subsequently incubated with each steroid for either 24 h or directly in cell extracts. STS mRNA and protein expression, and its subcellular localization were determined by semi-quantitative RT-PCR, immunoblotting, and confocal immunofluorescence microscopy. STS activity was evaluated by incubating homogenized breast cells with [(3)H]-E1S. The products E1 and E2 were separated by thin layer chromatography. STS was co-localized with the Golgi marker protein GM130 and the endoplasmic reticulum marker protein calnexin. Treatment did not significantly alter STS mRNA expression. STS protein expression was increased by each steroid in HBL-100 cells but by E2 only in MCF-7 cells. 24 h incubation with OrgOD14 and Org4094 did not alter STS activity in both cell lines. However, STS activity was significantly diminished in HBL-100 but slightly increased in MCF-7 cells by 24 h treatment with E2. "Direct" incubation of cell extracts, eliminating cellular regulation of metabolism, reduced estrogen biosynthesis regardless of cell line and treatment. In conclusion, the immediate reduction of estrogen biosynthesis by OrgOD14 is counteracted by an increased STS protein expression. On the contrary, E2 exerts a differential effect on STS in HBL-100 and MCF-7 cells. The transition from normal to malignant breast cells may be accompanied by an abolished autoregulation of local estrogen formation.
Breast Cancer Res Treat 2008 Apr
PMID:Differential effect of hormone therapy on E1S-sulfatase activity in non-malignant and cancerous breast cells in vitro. 1754 97

The synthetic retinoid N-(4-hydroxyphenyl)retinamide (4-HPR) induces apoptosis in a variety of cell lines and has shown promise as an anticancer agent both in vitro and in vivo. The clinical dose of 4-HPR, however, is limited by residual-associated toxicities, indicating a need for a less toxic drug. In this study, we show that 4-hydroxybenzylretinone (4-HBR), the unhydrolyzable analogue of 4-HPR, is effective in producing apoptosis in a variety of 4-HPR-sensitive cell lines, including breast cancer, neuroblastoma, and leukemia cells. We also show through the use of a pan-caspase inhibitor that this 4-HBR-induced apoptosis is dependent, at least in part, on caspase activity. 4-HBR is shown to exhibit binding to the retinoic acid receptors (RAR) at concentrations necessary to induce cell death and induces expression of all-trans-retinoic acid-responsive genes that can be blocked by a RAR pan-antagonist. However, through the use of this RAR pan-antagonist, 4-HBR-induced apoptosis and cell death is shown to be independent of the RAR signaling pathway. To further characterize the mechanism of action of 4-HBR, expression of the endoplasmic reticulum stress-induced genes GADD153 and Bcl-2-binding component 3 was examined. These mRNAs are shown to be rapidly induced in 4-HBR-treated and 4-HPR-treated breast cancer cells, and this up-regulation is also shown to be independent of the RARs. These results suggest that a stress-mediated apoptotic cascade is involved in the mechanism of action of these retinoids.
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PMID:The unhydrolyzable fenretinide analogue 4-hydroxybenzylretinone induces the proapoptotic genes GADD153 (CHOP) and Bcl-2-binding component 3 (PUMA) and apoptosis that is caspase- dependent and independent of the retinoic acid receptor. 1761 85

Sigma-2 receptor agonists have been shown to induce cell death via caspase-dependent and caspase-independent pathways. Unfortunately, there is little information regarding the molecular function of sigma-2 receptors that can explain these results. In this study, two fluorescent probes, SW107 and K05-138, were used to study the subcellular localization of sigma-2 receptors by two-photon and confocal microscopy. The results indicate that sigma-2 receptors colocalize with fluorescent markers of mitochondria, lysosomes, endoplasmic reticulum, and the plasma membrane in both EMT-6 mouse and MDA-MB-435 human breast cancer cells. The fluorescent probe, K05-138, was internalized rapidly, reaching a plateau of fluorescent intensity at 5 min. The internalization of K05-138 was reduced approximately 40% by phenylarsine oxide, an inhibitor of endocytosis. These data suggest that sigma-2 ligands are internalized, in part, by an endocytotic pathway. The localization of sigma-2 receptors in several organelles known to have a role in both caspase-dependent and caspase-independent pathways of cell death supports the conclusions of previous studies suggesting that sigma-2 receptor ligands should be evaluated as potential cancer chemotherapeutic agents.
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PMID:Subcellular localization of sigma-2 receptors in breast cancer cells using two-photon and confocal microscopy. 1763 81

Human epidermal growth factor receptor-2 (HER-2) overexpression in breast cancer occurs in 20% to 30% of patients with breast cancer. Trastuzumab (Herceptin) targets HER-2 tyrosine kinase receptors expressed on tumor cells and mediates anti-proliferative effects against HER-2-positive tumor cells. Adjuvant chemotherapy with trastuzumab has improved the prognosis of patients with HER-2 positive high-grade breast cancer. However, patients often experience appearance and proliferation of recurrent tumor cells after trastuzumab treatment. In this study, we report the successful establishment and characterization of a cell line (BTIC) derived from a patient with recurrent breast cancer after adjuvant chemotherapy with trastuzumab. Characteristics of the BTIC cell line were investigated by phase contrast or electron microscopic observations, chromosome analysis, xenotransplantation, immunohistochemistry and radioimmunoassay for tumor markers. We confirmed that the BTIC cell line grown as multilayered culture in culture dishes, has a poorly developed endoplasmic reticulum in the cytoplasm and some desmosomes. The population doubling time was approximately 44 hr. A graft in nude mouse after xenotransplantation was diagnosed as scirrhous carcinoma. Immunohistochemistry on cultured BTIC cells revealed that the BTIC cells were negative for estrogen receptor and progesterone receptor, and 30% positive for HER-2. Radioimmunoassay indicated secretion of HER-2 protein, NCC-ST-439 and CA15-3.
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PMID:Establishment and characterization of a cell line (BTIC) including HER-2-positive cells derived from pleural effusion of recurrent breast invasive ductal carcinoma, scirrhous type. 1764 28


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