UMLS:C0006142 - FACTA Search

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

This article focuses on the recent findings by Marsh and colleagues, and also discusses recent findings with regards to breast cancer. Taxanes are amongst the most active agents in the treatment of breast cancer. However, many tumors are intrinsically resistant. Therefore, it would be an enormous progress, if factors could be identified that reliably differentiate between taxane-sensitive and -resistant patients. Marsh and colleagues analyzed the CYP1B1*3 (Val432Leu) polymorphism in patients with high-risk stage III and IV breast cancer, who received dose-intense paclitaxel in combination with doxorubicin and cyclophosphamide. They report for the first time that patients with two leucine alleles in codon 432 of CYP1B1 experience a longer progression-free survival compared with patients with the Val/Leu or Val/Val genotypes. If confirmed in independent cohorts CYP1B1*3 may prove to be an important factor that helps to differentiate between paclitaxel-sensitive and resistant breast cancer patients. However, the mechanism behind the association between CYP1B1*3 and prognosis of paclitaxel-treated patients remains unclear. Several studies provide strong evidence that CYP1B1 does not influence tumor progression independently from paclitaxel chemotherapy, and that CYP1B1 itself does not alter paclitaxel resistance. In addition, CYP1B1 mRNA expression does not correlate with paclitaxel sensitivity of primary tumor cells. Although still speculative, a possible explanation is an association between CYP1B1*3 with still unknown factors that, on their part, influence paclitaxel sensitivity. In the future, studies with SNP chips and studies on the transcriptome, proteome and metabolome level should be performed in order to identify signatures differentiating between paclitaxel-sensitive and -resistant patients.
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PMID:Prediction of paclitaxel resistance in breast cancer: is CYP1B1*3 a new factor of influence? 1859 57

Hormone therapy, estrogen plus progestin (E+P) particularly, is associated with increased risk of breast cancer. Functionally relevant polymorphisms in genes involved in sex hormone metabolism may alter exposure to exogenous sex hormones and affect risk of postmenopausal breast cancer. We evaluated associations of common polymorphisms in genes involved in estrogen and/or progesterone metabolism, E+P use, and their interactions with breast cancer risk in a case-control study of postmenopausal women (324 cases; 651 controls) nested within the VITAL cohort. None of the polymorphisms studied was, by itself, statistically significantly associated with breast cancer risk. E+P use was significantly associated with increased breast cancer risk (> or =10 years versus never; odds ratio, 1.9; 95% confidence interval, 1.3-2.8; P(trend) = 0.0002). Statistically significant interactions between CYP1A1 Ile(462)Val (P(interaction) = 0.04), CYP1A1 MspI (P(interaction) = 0.003), CYP1B1 Val(432)Leu (P(interaction) = 0.007), CYP1B1 Asn(453)Ser (P(interaction) = 0.04) and PGR Val(660)Leu (P(interaction) = 0.01), and E+P use were observed. The increased risk of breast cancer associated with E+P use was greater among women with at least one rare allele of the CYP1A1 Ile(462)Val, CYP1A1 MspI, CYP1B1 Asn(453)Ser, and PGR Val(660)Leu polymorphisms than among women homozygous for the common allele of these polymorphisms. Risk of breast cancer increased little with increasing years of E+P use among women with at least one CYP1B1 Val(432) allele; a large increase in risk was seen among women homozygous for CYP1B1 Leu(432). Our results support the hypothesis that specific polymorphisms in genes involved in sex hormone metabolism may modify the effect of E+P use on breast cancer risk.
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PMID:Polymorphisms in genes involved in sex hormone metabolism, estrogen plus progestin hormone therapy use, and risk of postmenopausal breast cancer. 1862 28

The protective effects of iodine on breast cancer have been postulated from epidemiologic evidence and described in animal models. The molecular mechanisms responsible have not been identified but laboratory evidence suggests that iodine may inhibit cancer promotion through modulation of the estrogen pathway. To elucidate the role of iodine in breast cancer, the effect of Lugol's iodine solution (5% I(2), 10% KI) on gene expression was analyzed in the estrogen responsive MCF-7 breast cancer cell line. Microarray analysis identified 29 genes that were up-regulated and 14 genes that were down-regulated in response to iodine/iodide treatment. The altered genes included several involved in hormone metabolism as well as genes involved in the regulation of cell cycle progression, growth and differentiation. Quantitative RT-PCR confirmed the array data demonstrating that iodine/iodide treatment increased the mRNA levels of several genes involved in estrogen metabolism (CYP1A1, CYP1B1, and AKR1C1) while decreasing the levels of the estrogen responsive genes TFF1 and WISP2. This report presents the results of the first gene array profiling of the response of a breast cancer cell line to iodine treatment. In addition to elucidating our understanding of the effects of iodine/iodide on breast cancer, this work suggests that iodine/iodide may be useful as an adjuvant therapy in the pharmacologic manipulation of the estrogen pathway in women with breast cancer.
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PMID:Iodine alters gene expression in the MCF7 breast cancer cell line: evidence for an anti-estrogen effect of iodine. 1864 7

The study is concerned with identification of a relationship between levels of production and accumulation of compounds capable of hormonal and progenotoxic effects in mammary fat, on the one hand, and characteristics of tumor tissue in breast cancer, on the other. Mammary fat was sampled at a distance of 1.5-2 cm from tumor edge (79 pts.). Case histories were used to provide data on clinical stage, size, grade and regional lymph node involvement. Levels were assayed of leptin, adiponectin, tumor necrosis factor (TNF-alpha), interleukin-6 (IL-6), nitric oxide (NO), thiobarbiturate-reactive products (TBRP) and DNA oxidative damage marker (8-OH-dG) from 4hr-incubates of fat tissue culture. Mammary fat aromatase was assayed by radiometrical means while macrophage-assisted fat infiltration (CD68) and estrogen-4-hydroxylase (CYP1B1) expression were evaluated immunohistochemically. Radio-competitive and immunohistochemical methods were used to assay estrogen (ER) and progesterone (PR) receptor levels in tumor and tumor-related expression of cytokeratins 5/6 ("basal") and 7/8 ("luminal" epithelium), respectively. As far as hormonal properties of mammary fat were concerned, there were direct correlations between aromatase concentration, on the one hand, and tumor stage and size, on the other, and adiponectin secretion and CK7 expression in tumor. Besides, an inverse correlation was found between mammary fat-mediated release of leptin and adiponectin, on the one hand, and stage and regional lymph node involvement, on the other. The following main relationships were identified by comparison of the clinico-biological characteristics of tumor and markers of proinflammatory/progenotoxic properties of mammary adipose tissue: tendency toward direct correlation with IL-6 and 8-OH-dG in fat (tumor progress stage); direct correlation with TNF-alpha secretion rate (malignancy grade); lymph node involvement--tendency toward direct correlation with NO generation; CK5 expression in tumor--tendency toward direct correlation with 8-OH-dG, TBRP and CD68 fat infiltration; CK7 expression in tumor--tendency toward inverse correlation with NO generation in adipose tissue; ER-negative phenotype of tumor--tendency toward higher generation of TBRP, NO and TNF/leptin in fat. Hence, shift toward predominance of proinflammatory/progenotoxic properties of mammary adipose tissue (adipogenotoxicosis) is associated with signs of less favorable course of tumor process in the mammary gland which calls for working out adequate measures.
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PMID:[Progenotoxic shift in mammary adipose tissue (adipogenotoxicosis): association with clinical and biological characteristics of breast cancer]. 1865 33

Breast cancer is the most common female cancer and the second cause of cancer death in women. Despite recent breakthroughs, much of the etiology of this disease is unknown and the most important risk factor, i.e., exposure to endogenous and exogenous estrogen throughout life cannot explain the heterogeneity of prognosis nor clinical features of patients. Recently, many gene polymorphisms in the metabolism of breast cancer have been described as possible neoplasm etiologic factors. This review is an attempt to summarize the current knowledge about these polymorphisms and to determine new target genes for diagnosis and treatment of the disease. Polymorphisms in the genes CYP17, CYP19, CYP1A1, CYP1A2, CYP1B1, UGT1A1, SULT1A1, 17-hydroxysteroid-dehydrogenase, COMT, GST, ESR1, and ESR2 are described.
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PMID:Genetic polymorphisms, the metabolism of estrogens and breast cancer: a review. 1871 61

We have previously shown that tamoxifen+epigallocatechin gallate (EGCG) is synergistically cytotoxic towards oestrogen receptor (ER)-negative breast cancer cells. To determine if this response would correlate with significant tumour suppression in vivo, athymic nude female mice were implanted with MDA-MB-231 cells and treated with tamoxifen, EGCG, EGCG+tamoxifen, or vehicle control for 10 weeks. Tumour volume in EGCG- (25 mg kg(-1))+tamoxifen (75 microg kg(-1))-treated mice decreased by 71% as compared with vehicle control (P<0.05), whereas tumour weight was decreased by 80% compared with control (P<0.01). Epigallocatechin gallate treatment did not alter ER protein expression in MDA-MB-231 cells and thus was not a mechanism for the observed tumour suppression. However, western blotting of tumour extracts demonstrated that epidermal growth factor receptor (EGFR; 85% lower than control), pEGFR (78% lower than control), mammalian target of rapamycin (mTOR; 78% lower than control), and CYP1B1 (75% lower than control) were significantly lower after the combination treatment as compared with all other treatments. Nuclear factor-kappaB (NF-kappaB), b-Raf, p-MEK, S6K, 4EBP1, Akt, vascular EGFR-1 (VEGFR-1) and VEGF expressions were decreased in control but not in the individual treatments, whereas MEK, phospholipase D 1/2, TGF alpha, and ERK expressions were not changed after any treatment. The results demonstrate that tamoxifen at realistic doses (75 mug kg(-1)) can suppress the growth of ER-negative breast cancer when combined with EGCG. In addition, the dominant mechanism for tumour suppression is the concomitant decrease in tumour protein expressions of mTOR and the EGFR.
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PMID:A new role for tamoxifen in oestrogen receptor-negative breast cancer when it is combined with epigallocatechin gallate. 1879 54

Cytochrome P450 (CYP) 1A1 and CYP1B1 are inducible by 2,3,7,8-tetrachlorodibenzo-p-dioxin (dioxin) in the human breast cancer cell line, MCF-7. Since CYP1A1 was inducible to a much greater degree than CYP1B1, we hypothesized that there may be differences in coactivator recruitment to the promoter and/or enhancer regions of these genes. Dioxin treatment leads to recruitment of the aryl hydrocarbon receptor to the enhancer regions but not to the proximal promoter regions of both the CYP1A1 and CYP1B1 genes. On the other hand, dioxin treatment facilitated recruitment of RNA polymerase II to the promoters but not the enhancer regions. Dioxin treatment also elicited recruitment of the transcriptional coactivators, steroid receptor coactivator 1 (SRC-1) and steroid receptor coactivator 2 (SRC-2) and p300, which possess intrinsic histone acetyltranferase activities, to both genes, whereas Brahma (BRM)/Switch 2-related gene 1 (BRG-1), a subunit of nucleosomal remodeling factors, was recruited more robustly to CYP1A1 relative to CYP1B1. Small inhibitory RNA-mediated knockdown of p300 and SRC-2 adversely affected dioxin induction of both genes, whereas knockdown of BRM/BRG-1 reduced CYP1A1 induction but had little, if any, effect on CYP1B1 induction. These results suggest that nucleosomal remodeling is less significant for dioxin-mediated induction of CYP1B1 than that of CYP1A1 and may be related to the more modest inducibility of the former. Interestingly, simultaneous knockdown of SRC-2 and BRM/BRG-1 had no greater effect on CYP1A1 induction than knockdown of each coactivator individually, while simultaneous knockdown of p300 and BRM/BRG-1 had a much greater effect than knockdown of each individual gene, suggesting that the recruitment of SRC-2 to CYP1A1 depends upon BRM/BRG-1, while the recruitments of p300 and BRM/BRG-1 are independent of each other. These observations provide novel insights into the functional roles of the endogenous coactivators in dioxin induction of the human CYP1A1 and CYP1B1 genes in their natural chromosomal configurations.
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PMID:Roles of coactivator proteins in dioxin induction of CYP1A1 and CYP1B1 in human breast cancer cells. 1884 20

Breast cancer is a major cause of death worldwide. Amongst the various forms of treatment chemoprevention is favoured and natural products such as the dietary flavonoids have been examined for their cancer preventative activity. In this study we investigated the anticancer activity of the flavonoid diosmetin, as a result of cytochrome P450 CYP1 metabolism. Diosmetin was metabolized to luteolin via an aromatic demethylation reaction on the B-ring from CYP1A1, CYP1B1 and the hepatic isozyme CYP1A2. CYP1A1 and CYP1A2 also produced additional unidentified metabolites. CYP1B1 showed the lowest apparent KM and CYP1A1 the highest apparent Kcat. Diosmetin was also metabolized to luteolin in estrogen receptor positive breast cell-line (MCF-7 cells) preinduced for 24 h with the potent CYP1 inducer 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Treatment of MCF-7 cells with TCDD caused bioactivation of diosmetin enhancing its cytotoxicity. Taken together these data suggest that the flavonoid diosmetin is metabolised to the more active molecule luteolin by CYP1 family enzymes.
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PMID:Bioactivation of the phytoestrogen diosmetin by CYP1 cytochromes P450. 1897 53

Southeast Asian women have a lower incidence of breast cancer than their counterparts in the West. Epidemiological studies have indicated that soya consumption may be a contributing factor. Carcinogenesis is a process involving multiple stages. The present review attempts to fit the cellular mechanisms attributed to soya isoflavones into these different stages. Many cell-culture studies have reported the growth-inhibitory effect of soya isoflavones; however, with the non-physiological concentrations employed in these studies it would be difficult to explain the protection mechanisms observed in epidemiological studies. Our laboratory has previously found that genistein inhibits cytochrome P450 (CYP)1A1 and CYP1B1. The inhibition implies that soya consumption may have the potential to prevent chemical carcinogenesis. The preferential inhibition of CYP1B1 may also block the oestrogen-initiated carcinogenesis. The antagonism of oestrogen receptor (ER) binding can affect the cell-proliferative phase, which is likely to be important in the promotion stage of breast cancer. Since our laboratory and others have indicated that genistein at physiological concentrations has no effect on the downstream activities of ER binding, the antagonism of ER is not likely to be a contributing factor in the disease prevention. Moreover, soya isoflavones cannot inhibit aromatase (CYP19), which is the enzyme responsible for oestrogen synthesis. In the present review various cellular activities altered by soya isoflavones are discussed.
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PMID:Dietary soya isoflavones and breast carcinogenesis: a perspective from a cell-culture model. 1907 5

Exposure to estrogens is a risk factor for breast cancer. Specific estrogen metabolites may initiate breast cancer and other cancers. Genotoxicity may be caused by cytochrome P450 (CYP)-mediated oxidation of catechol estrogens to quinones that react with DNA to form depurinating estrogen-DNA adducts. CYP1B1 favors quinone formation by catalyzing estrogen 4-hydroxylation, whereas NAD(P)H quinone oxidoreductase 1 (NQO1) catalyzes the protective reduction of quinones to catechols. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) induces CYP1B1 expression through the aryl hydrocarbon receptor (AhR). Resveratrol has anticancer effects in diverse in vitro and in vivo systems and is an AhR antagonist that decreases CYP expression but induces NQO1 expression. The chemopreventive effect of resveratrol on breast cancer initiation was investigated in MCF-10F cells. Its effects on estrogen metabolism and formation of estrogen-DNA adducts were analyzed in culture medium by high-performance liquid chromatography, whereas its effects on CYP1B1 and NQO1 were determined by immunoblotting and immunostaining. The antitransformation effects of resveratrol were also examined. TCDD induced expression of CYP1B1 and its redistribution in the nucleus and cytoplasm. Concomitant treatment with resveratrol dose-dependently suppressed TCDD-induced expression of CYP1B1, mainly in the cytoplasm. Resveratrol dose- and time-dependently induced expression of NQO1. NQO1 is mainly in the perinuclear membrane of control cells, but resveratrol induced NQO1 and its intracellular redistribution, which involves nuclear translocation of nuclear factor erythroid 2-related factor 2. Resveratrol decreased estrogen metabolism and blocked formation of DNA adducts in cells treated with TCDD and/or estradiol. Resveratrol also suppressed TCDD and/or estradiol-induced cell transformation. Thus, resveratrol can prevent breast cancer initiation by blocking multiple sites in the estrogen genotoxicity pathway.
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PMID:Resveratrol prevents estrogen-DNA adduct formation and neoplastic transformation in MCF-10F cells. 1913 46

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