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

Cells contain numerous pathways designed to protect them from the genomic instability or toxicity that can result when their DNA is damaged. The p53 tumor suppressor is particularly important for regulating passage through G1 phase of the cell cycle, while other checkpoint regulators are important for arrest in S and G2 phase. Tumor cells often exhibit defects in these checkpoint proteins, which can lead to hypersensitivity; proteins in this class include ataxia-telangiectasia mutatated (ATM), Meiotic recanbination 11 (Mre11), Nijmegen breakage syndrome 1 (Nbs 1), breast cancer susceptibility genes 1 and 2 (BRCA1), and (BRCA2). Consequently, tumors should be assessed for these specific defects, and specific therapy prescribed that has high probability of inducing response. Tumors defective in p53 are frequently considered resistant to apoptosis, yet this defect also provides an opportunity for targeted therapy. When their DNA is damaged, p53-defective tumor cells preferentially arrest in S or G2 phase where they are susceptible to checkpoint inhibitors such as caffeine and UCN-01. These inhibitors preferentially abrogate cell cycle arrest in p53-defective cells, driving them through a lethal mitosis. Wild type p53 can prevent abrogation of arrest by elevating levels of p21(waf1) and decreasing levels of cyclins A and B. During tumorigenesis, tumor cells frequently loose checkpoint controls and this facilitates the development of the tumor. However, these defects also represent an Achilles heel that can be targeted to improve current therapeutic strategies.
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PMID:Cell cycle checkpoints and their impact on anticancer therapeutic strategies. 1474 82

Much attention has been paid to the relation between diet and breast cancer risk. Because benign breast disease (BBD), particularly atypical hyperplasia (AH), is a marker of increased breast cancer risk, studies of diet and BBD may provide evidence about the effect of diet at an early stage in the process of breast carcinogenesis. We evaluated the relationship between fat, fiber, antioxidant and caffeine intake and incidence of non-proliferative BBD, proliferative BBD without atypia and AH in the Nurses' Health Study II. We calculated rate ratios (RR) and 95% confidence intervals (95% CI) for each quartile of energy-adjusted intake using the lowest quartile as reference. There was no increase in risk of BBD with increasing fat intake, rather increasing vegetable fat was associated with a significant reduction in the rate of proliferative BBD without atypia. There was no significant association between any type of BBD and micronutrient intake. High caffeine consumption was positively associated (RR = 2.46, 95% CI 1.11-5.49 for the highest quartile), and use of multivitamin supplements inversely associated (RR = 0.57, 95% CI 0.33-0.98) with risk of AH although these analyses were based on small numbers. These data do not support the hypothesis that higher fat consumption increases risk of BBD, with or without atypia, and also provide little evidence for a major role of antioxidants in the development of breast disease. They do, however, raise the possibility that high caffeine intake may increase, and use of vitamin supplements may decrease risk of developing AH.
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PMID:A prospective study of diet and benign breast disease. 1524 20

The mammalian target of rapamycin (mTOR) functions with raptor and mLST8 in a signaling complex that controls rates of cell growth and proliferation. Recent results indicate that an inhibitor of the Ras signaling pathway, farnesylthiosalicylic acid (FTS), decreased phosphorylation of the mTOR effectors, PHAS-I and S6K1, in breast cancer cells. Here we show that incubating 293T cells with FTS produced a stable change in mTOR activity that could be measured in immune complex kinase assays using purified PHAS-I as substrate. Similarly, FTS decreased the PHAS-I kinase activity of mTOR when added to cell extracts or to immune complexes containing mTOR. Incubating either cells or extracts with FTS also decreased the amount of raptor that coimmunoprecipitated with mTOR, although having relatively little effect on the amount of mLST8 that coimmunoprecipitated. The concentration effect curves of FTS for inhibition of mTOR activity and for dissociation of the raptor-mTOR complex were almost identical. Caffeine, wortmannin, LY294002, and rapamycin-FKBP12 also markedly inhibited mTOR activity in vitro, but unlike FTS, none of the other mTOR inhibitors appreciably changed the amount of raptor associated with mTOR. Thus, our findings indicate that FTS represents a new type of mTOR inhibitor, which acts by dissociating the functional mTOR-raptor signaling complex.
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PMID:Farnesylthiosalicylic acid inhibits mammalian target of rapamycin (mTOR) activity both in cells and in vitro by promoting dissociation of the mTOR-raptor complex. 1545 49

Hormone Replacement Therapy (HRT), once considered as the gold standard of treatment of menopausal symptoms and osteoporosis, introduced about seventy years ago still continuing with lot of controversies. Menopause, a transitional period of women's life, is not an illness when oestrogen level falls leading to its consequences. Results of earlier observational studies showed beneficial effects of HRT including cardiovascular protection. But all recent randomized controlled trials have failed to prove these positive effects, rather increases the cardiovascular risk and breast cancer. Women's Health Initiative(WHI), one of the recent randomized controlled trials was stopped prematurely in 2002 due to unfavorable risk-benefit ratio. HRT is not the only way of treating the menopausal symptoms and other consequences of estrogen deficiency. There are suitable alternatives without bearing the risk of HRT. Vasomotor symptoms with hot flushes and sweating experienced by about 75 percent of menopausal women can be treated with alternatives like phyto-estrogens, selective estrogen receptor modulators (SERMs), clonidine, selective serotonin reuptake inhibitors, acupuncture, exercise, behavioral therapy etc. HRT is no longer considered as the first line of treatment of postmenopausal osteoporosis. It can be treated with alternatives like regular weight bearing exercise, balanced calcium rich diet, maintaining weight, avoidance of bone robbers, (like excess alcohol, caffeine, smoking), use of SERMs etc. Use of HRT should be individualized and rationalized considering its risks and benefits.
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PMID:Evaluation of hormone replacement therapy. 1605 16

The high mobility group A2 (HMGA2) protein belongs to the architectural transcription factor HMGA family, playing a role in chromosomal organization and transcriptional regulation. We and others have previously reported that ectopic HMGA2 expression is associated with neoplastic transformation and anchorage-independent cell proliferation. Here, we reported a correlation between increased HMGA2 expression and enhanced chemosensitivity towards topoisomerase II inhibitor, doxorubicin, in breast cancer cells. Using cells exhibiting differential HMGA2 expression and small interfering RNA technique, we showed that HMGA2 expression modulates cellular response to the genotoxicity of DNA double-strand breaks. Notably, HMGA2 enhances doxorubicin-elicited cell cycle delay in sub-G1 and G2-M and augments cell cycle dysregulation on cotreatment of doxorubicin and caffeine. We further reported that HMGA2 induces a persistent Ser139 phosphorylation of histone 2A variant X, analogous to the activation by doxorubicin-mediated genotoxic stress. Moreover, this HMGA2-dependent enhancement of cytotoxicity is further extended to other double-strand breaks elicited by cisplatin and X-ray irradiation and is not restricted to one cell type. Together, we postulated that the enhanced cytotoxicity by double-strand breaks in HMGA2-expressing cells is mediated, at least in part, through the signaling pathway of which the physiologic function is to maintain genome integrity. These findings should contribute to a greater understanding of the role of HMGA2 in promoting tumorigenesis and conveying (chemo)sensitivity towards doxorubicin and other related double-strand breaks.
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PMID:High mobility group A2 potentiates genotoxic stress in part through the modulation of basal and DNA damage-dependent phosphatidylinositol 3-kinase-related protein kinase activation. 1606 42

We completed a phase I trial of indole-3-carbinol (I3C) in 17 women (1 postmenopausal and 16 premenopausal) from a high-risk breast cancer cohort. After a 4-week placebo run-in period, subjects ingested 400 mg I3C daily for 4 weeks followed by a 4-week period of 800 mg I3C daily. These chronic doses were tolerated well by all subjects. Hormonal variables were measured near the end of the placebo and dosing periods, including determination of the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio. Measurements were made during the follicular phase for premenopausal women. Serum estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, and sex hormone binding globulin showed no significant changes in response to I3C. Caffeine was used to probe for cytochrome P450 1A2 (CYP1A2), N-acetyltransferase-2 (NAT-2), and xanthine oxidase. Comparing the results from the placebo and the 800 mg daily dose period, CYP1A2 was elevated by I3C in 94% of the subjects, with a mean increase of 4.1-fold. In subjects with high NAT-2 activities, these were decreased to 11% by I3C administration but not altered if NAT-2 activity was initially low. Xanthine oxidase was not affected. Lymphocyte glutathione S-transferase activity was increased by 69% in response to I3C. The apparent induction of CYP1A2 was mirrored by a 66% increase in the urinary 2-hydroxyestrone/16alpha-hydroxyestrone ratio in response to I3C. The maximal increase was observed with the 400 mg daily dose of I3C, with no further increase found at 800 mg daily. If the ratio of hydroxylated estrone metabolites is a biomarker for chemoprevention, as suggested, then 400 mg I3C daily will elicit a maximal protective effect.
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PMID:A phase I study of indole-3-carbinol in women: tolerability and effects. 1610 43

Caffeine has been suggested as a possible risk factor for breast cancer, potentially through its effect of facilitating the development of benign breast disease. However, coffee and tea also contain polyphenols, which exhibit anticarcinogenic properties. A hospital-based, case-control study was conducted to evaluate the role of coffee, decaffeinated coffee, and black tea in breast cancer etiology. Study participants included 1932 cases with primary, incident breast cancer and 1895 hospital controls with nonneoplastic conditions. All participants completed a comprehensive epidemiological questionnaire. Among premenopausal women, consumption of regular coffee was associated with linear declines in breast cancer risk (P for trend = 0.03); consumers of >or=4 cups/d experienced a 40% risk reduction (odds ratio = 0.62, 95% CI 0.39-0.98). No clear associations between intake of black tea or decaffeinated coffee and breast cancer risk were noted among premenopausal women, although black tea was associated with a protective effect unique to a subsample of cases with lobular histology. Among postmenopausal women, breast cancer risk was not associated with consumption of coffee, tea, or decaffeinated coffee. Results among postmenopausal women did not differ by histologic subtype. Our findings support a protective effect of coffee intake on premenopausal, but not postmenopausal breast cancer risk. Further studies are warranted to confirm these findings.
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PMID:Consumption of coffee, but not black tea, is associated with decreased risk of premenopausal breast cancer. 1636 77

Several different cancer studies have indicated that lymphocyte mutagen sensitivity is a marker of DNA repair deficiency and increased cancer risk. We have used a mutagen sensitivity assay (MSA) measuring gamma-radiation-induced chromosomal aberrations in freshly cultured lymphocytes and assessed breast cancer risk in African-American women. Concurrently, we conducted duplicate cultures in the presence of caffeine, which overrides G(2) arrest in cultured cells, decreases time to DNA repair, and hence increases the aberration rate. In comparison with the non-caffeine-treated cells, we are conceptually segregating the contribution of DNA repair and time for DNA repair as individual susceptibility phenotypes. Blood samples were obtained from 61 cases and 86 controls at Howard University Hospital. Two sets of whole-blood cultures were established and gamma-irradiated (1 Gy) at 67 hours, one of which was treated with caffeine (1 mg/mL). Thereafter, cultures were processed for obtaining metaphase spreads. Fifty metaphases were screened for chromatid breaks. The mean breaks per cell (MBPC) for cases (0.34 +/- 0.15) was significantly greater than for controls (0.24 +/- 0.12; P < 0.0001). Using the 75th percentile value of controls as a cutoff to define mutagen sensitivity, the sensitive individuals had an odds ratio of 4.5 (95% confidence intervals, 2.2-9.1) for breast cancer compared with individuals that were not sensitive. The adjusted odds ratio was 3.3 (95% confidence intervals, 0.147-73.917), which was statistically significant but was limited by the small number of subjects. The results for caffeine co-culture were not predictive of breast cancer (MBPC: cases, 1.6 +/- 0.9 versus controls, 1.5 +/- 0.8; P = 0.8663). Comparing the MBPC for caffeine and non-caffeine cultures, there was a correlation in controls (n = 79; Spearman r = 0.4286; P < 0.0001), but not in cases (n = 58; Spearman r = 0.06609; P = 0.6221). This study indicates that the MSA phenotype is a risk factor for breast cancer in African-American women, with a significant effect observable even in small studies. The use of caffeine did not enhance the predictivity of MSA, but the correlation with non-caffeine cultures in controls indicates that the MSA phenotype is due to both DNA repair and G(2) arrest capacity.
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PMID:gamma-Radiation-induced chromosomal mutagen sensitivity is associated with breast cancer risk in African-American women: caffeine modulates the outcome of mutagen sensitivity assay. 1653 98

The aryl hydrocarbon receptor (AhR) is a key regulator of the transcriptional expression for the cytochrome P450 1 (CYP1) genes. CYP1A2 is one of the major CYP1 enzymes that catalyse 2-hydroxylation of estrogen, a hormone that plays a critical role in the etiology of breast cancer. In this study, we investigated whether two common polymorphisms in these two genes, CYP1A2*1F and AhR Lys554Arg, were associated with breast cancer risk in 1090 cases and 1183 controls, a subset of the population-based case-control study, the Shanghai Breast Cancer Study. Caffeine tests were performed in vivo in a subset of 236 study subjects to investigate the relationship of these two polymorphisms with CYP1A2 activity. For the AhR gene, the A (Lys) allele was associated with a decreased risk of breast cancer. Using the genotype GG as reference, odds ratios of 0.82 [95% confidence interval (CI)=0.69-0.99] for the AG genotype and 0.76 (95% CI=0.58-1.01) for the AA genotype (P for trend=0.018) were obtained. However, no association was observed between CYP1A2 genotypes and breast cancer risk, although the CYP1A2*1F polymorphism was found to be related to CYP1A2 activity. The geometric mean values for the caffeine metabolites ratio were 2.90, 2.30, and 1.95 for CC, AC, and AA genotypes, respectively (P for trend=0.024). In conclusion, the results from our study suggest that the AhR Lys554Arg polymorphism may be a genetic susceptibility factor for breast cancer, whereas CYP1A2*1F, which is a potentially functional single nucleotide polymorphism, may not be related to breast cancer risk.
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PMID:Population-based case-control study of AhR (aryl hydrocarbon receptor) and CYP1A2 polymorphisms and breast cancer risk. 1653 70

Cyclophosphamide (CPA) and adriamycin (ADR) are widely used drugs for cancer chemotherapy. It has been reported that CPA and ADR singly or in combination could alter activities of a variety of drug-metabolizing enzymes in animals via multiple mechanisms. However, the effects of CPA/ADR on drug metabolism are largely unknown in human beings. Losartan metabolism has been suggested as a marker for determination of CYP2C9 activity. Caffeine is a commonly used probe to assess the metabolic activities of CYP1A2, CYP2A6, N-acetyltransferase 2 (NAT2) and xanthine oxidase (XO). The present study was designed to analyze the effects of CPA/ADR on these drug-metabolizing enzymes by using losartan and caffeine as probe drugs. A single oral dose of 25 mg losartan and a cup of instant coffee was given to 15 breast cancer patients on three occasions (before, and 2-4 h and 3 weeks after the adjuvant CPA/ADR chemotherapy [600 mg CPA/m2/day, 60 mg ADR/m2/day]). Losartan, caffeine and their metabolites were analyzed by using high-pressure liquid chromatography. When compared with baseline, CYP1A2 activity was increased by 20% and CYP2C9 activity was decreased by 315% 3 weeks after the administration of CPA/ADR chemotherapy (p = 0.05). The chemotherapy did not change the activities of CYP2A6, NAT2 or XO. CPA/ADR treatment caused a differential effect on drug-metabolizing enzyme activities, and this may contribute to predicting the efficacy and toxicity of chemotherapeutics, as well as understanding the drug-drug interactions.
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PMID:Differential alteration of drug-metabolizing enzyme activities after cyclophosphamide/adriamycin administration in breast cancer patients. 1734 41


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