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)

Candidate gene association studies to detect breast cancer susceptibility loci have yielded few positive associations. Therefore, it is more likely that variants in many genes along related biological pathways combine to influence breast cancer risk. A strong candidate pathway is that of p53-mediated cell-cycle control, DNA repair, and apoptosis. The two major proteins along this pathway are p53 and its negative regulator MDM2. Functional polymorphisms in both genes have been identified. The -309 SNP in MDM2 is associated with increased MDM2 transcription. The Arg72Pro polymorphism of p53 alters the transcription of p53 target genes and modifies the apoptotic potential of cells. Both polymorphisms have been studied with respect to breast cancer risk, with inconclusive results. We have genotyped both polymorphisms in the breast cancer cases and controls nested within the Nurses' Health Study and Nurses' Health Study II. Neither SNP is independently associated with overall breast cancer risk. Some indication of gene-by-gene interaction was observed; however, no consistent direction of interaction was apparent.
 ...
PMID:The p53 Arg72Pro and MDM2 -309 polymorphisms and risk of breast cancer in the nurses' health studies. 1738 21

Association studies in large series of breast cancer patients can be used to identify single-nucleotide polymorphisms (SNP) contributing to breast cancer susceptibility. Previous studies have suggested associations between variants in TP53 (R72P) and MDM2 (SNP309) and cancer risk. Data from molecular studies suggest a functional interaction between these genes. We therefore investigated the effect of TP53 R72P and MDM2 SNP309 on breast cancer risk and age at onset of breast cancer in a pooled series of 5,191 cases and 3,834 controls from the Breast Cancer Association Consortium (BCAC). Breast cancer risk was not found to be associated with the combined variant alleles [odds ratio (OR), 1.00; 95% confidence interval (95% CI), 0.81-1.23]. Estimated ORs were 1.01 (95% CI, 0.93-1.09) per MDM2 SNP309 allele and 0.98 (95% CI, 0.91-1.04) for TP53 R72P. Although we did find evidence for a 4-year earlier age at onset for carriers of both variant alleles in one of the breast cancer patient series of the BCAC (the German series), we were not able to confirm this effect in the pooled analysis. Even so, carriers of both variant alleles did not have different risk estimates for bilateral or estrogen receptor-positive breast cancer. In conclusion, in this large collaborative study, we did not find an association of MDM2 SNP309 and TP53 R72P, separately or in interaction, with breast cancer. This suggests that any effect of these two variants would be very small and possibly confined to subgroups that were not assessed in our present study.
 ...
PMID:Do MDM2 SNP309 and TP53 R72P interact in breast cancer susceptibility? A large pooled series from the breast cancer association consortium. 1790 70

A functional single nucleotide polymorphism in the promoter of the MDM2 gene, SNP309 (T>G), was recently found to accelerate tumorigenesis in early onset cancer cases. The SNP309 G-allele, introduces an SP1 site in the MDM2 promoter, resulting in enhanced MDM2 expression and activity. Thus, the G-allele of MDM2 SNP309 may represent a cancer predisposing allele. In this report, we assessed the role of SNP309 as a modifier of mutant BRCA1/BRCA2 alleles in inherited breast and ovarian cancer cases among Ashkenazi-Jewish (AJ) women. We genotyped several subsets of AJ women: 138 healthy women, 140 affected BRCA1/2 mutation carriers, 120 asymptomatic BRCA1/2 mutation carriers and 187 sporadic breast cancer patients. The frequency of GG genotype of SNP309 was similar among the different groups. Interestingly, we found almost three times higher frequency of the GG genotype among BRCA1/2 carriers diagnosed with breast and/or ovarian cancer at or under the age of 51 years compared with carriers diagnosed with cancer above the age of 51 years (allele frequency, P = 0.019). The GG genotype was significantly associated with breast and ovarian cancer risk among BRCA1/2 carriers diagnosed before 51 years of age (OR, 3.93; 95% CI, 1.41-10.90, P = 0.009). No significant difference in frequency of the GG genotype was observed between early and late onset non-carrier cancer patients and no association with risk, OR, 1.30; 95% CI 0.69-2.47, P = 0.419). These data suggest that MDM2 SNP309 acts as a modifier of mutant BRCA1/2 mutant alleles in AJ and may accelerate breast and ovarian carcinogenesis in genetically predisposed individuals.
Breast Cancer Res Treat 2008 Oct
PMID:MDM2 SNP309 accelerates breast and ovarian carcinogenesis in BRCA1 and BRCA2 carriers of Jewish-Ashkenazi descent. 1802 75

NUMB is a cell fate determinant, which, by asymmetrically partitioning at mitosis, controls cell fate choices by antagonising the activity of the plasma membrane receptor of the NOTCH family. NUMB is also an endocytic protein, and the NOTCH-NUMB counteraction has been linked to this function. There might be, however, additional functions of NUMB, as witnessed by its proposed role as a tumour suppressor in breast cancer. Here we describe a previously unknown function for human NUMB as a regulator of tumour protein p53 (also known as TP53). NUMB enters in a tricomplex with p53 and the E3 ubiquitin ligase HDM2 (also known as MDM2), thereby preventing ubiquitination and degradation of p53. This results in increased p53 protein levels and activity, and in regulation of p53-dependent phenotypes. In breast cancers there is frequent loss of NUMB expression. We show that, in primary breast tumour cells, this event causes decreased p53 levels and increased chemoresistance. In breast cancers, loss of NUMB expression causes increased activity of the receptor NOTCH. Thus, in these cancers, a single event-loss of NUMB expression-determines activation of an oncogene (NOTCH) and attenuation of the p53 tumour suppressor pathway. Biologically, this results in an aggressive tumour phenotype, as witnessed by findings that NUMB-defective breast tumours display poor prognosis. Our results uncover a previously unknown tumour suppressor circuitry.
 ...
PMID:NUMB controls p53 tumour suppressor activity. 1817 99

Sporadic breast cancer in women <40 years is uncommon in Caucasians, in contrast to a much earlier onset in Chinese Asians. However, the molecular determinants for this earlier onset are unclear. It has been reported that SNP309 in the promoter of MDM2, the negative regulator of p53, affects the onset age of cancers in females. Essentially, the G allele, rather than the T allele, has been suggested to accelerate the age of cancer onset. Hence, we examined if MDM2 and p53 polymorphisms would be determinants of the early onset phenomenon in Chinese women. Our results indicate that the MDM2 SNP309 G allele is more prevalent in the Chinese population compared with reported frequencies in Caucasians, and increases breast cancer risk of both sporadic cases and those with family history. However, it was the T/T genotype that was associated with earlier onset age of sporadic breast cancers in contrast to the G allele that was associated with the familial cases. Though p53 codon 72 single-nucleotide polymorphism (SNP) did not affect general cancer risk or age of onset, arginine homozygozity, in contrast to proline homozygozity, was found to decrease breast cancer risk in the later onset sporadic cases. Both SNP309 and codon 72 polymorphisms did not affect the stage of cancer. Together, the data suggest that though the MDM2 SNP309 G allele is a risk factor for breast cancer, it does not accelerate, but delays the onset of the sporadic disease in Chinese women, highlighting that differences in ethnicity and family history may influence the role of MDM2 SNP309 in cancer susceptibility.
 ...
PMID:MDM2 SNP309 G allele increases risk but the T allele is associated with earlier onset age of sporadic breast cancers in the Chinese population. 1828 Dec 48

Recent progress in diagnostic tools allows many breast cancers to be detected at an early preinvasive stage. Thus, a better understanding of the molecular basis of early breast cancer progression is essential. Previously, we discovered that 14-3-3 zeta is overexpressed in >40% of advanced breast cancers, and this overexpression predicts poor patient survival. Here, we examined at what stage of breast disease 14-3-3 zeta overexpression occurs, and we found that increased expression of 14-3-3 zeta begins at atypical ductal hyperplasia, an early stage of breast disease. To determine whether 14-3-3 zeta overexpression is a decisive early event in breast cancer, we overexpressed 14-3-3 zeta in MCF10A cells and examined its effect in a three-dimensional culture model. We discovered that 14-3-3 zeta overexpression severely disrupted the acini architecture resulting in luminal filling. Proper lumen formation is a result of anoikis, apoptosis due to detachment from the basement membrane. We found that 14-3-3 zeta overexpression conferred resistance to anoikis. Additionally, 14-3-3 zeta overexpression in MCF10A cells and in mammary epithelial cells (MEC) from 14-3-3 zeta transgenic mice reduced expression of p53, which is known to mediate anoikis. Mechanistically, 14-3-3 zeta induced hyperactivation of the phosphoinositide 3-kinase/Akt pathway which led to phosphorylation and translocation of the MDM2 E3 ligase resulting in increased p53 degradation. Ectopic expression of p53 restored luminal apoptosis in 14-3-3 zeta-overexpressing MCF10A acini in three-dimensional cultures. These data suggest that 14-3-3 zeta overexpression is a critical event in early breast disease, and down-regulation of p53 is one of the mechanisms by which 14-3-3 zeta alters MEC acini structure and increases the risk of breast cancer.
 ...
PMID:14-3-3 zeta down-regulates p53 in mammary epithelial cells and confers luminal filling. 1833 56

The mdm2 gene encodes several protein isoforms with different molecular weights (p90, p80, p76 and p57). MDM2 p90 (usually considered to be the major MDM2 protein) binds to and inactivates P53. We have recently shown that growth inhibition of MCF-7 human breast cancer cells by progesterone is associated with P53 down-regulation. In this work, we analyzed the expression pattern of MDM2 proteins in three human breast cancer cell lines by western blotting with anti-MDM2 antibodies. We found a prominent expression of MDM2 p57 protein in cell lines which have non-functional P53 protein (T47D and MDA-MB-231) as compared to the p90, p80 isoforms, whereas p90 was the major protein isoform in MCF-7 cells that contain functional P53 protein. When MCF-7 cells were treated with 100 nM of progesterone, MDM2 p90 was inhibited but the highly expressed MDM2 p57 isoform was not. The inhibition of MDM2 p90 protein by progesterone was abrogated in MCF-7 cells transfected with a P53 expressing vector. To our knowledge, this is the first report linking progesterone-induced growth inhibition with down-regulation of the MDM2 protein. We present evidence that reestablishing of P53 expression by transient transfection of P53 cDNA in these cells enhances the expression level of MDM2 p90 isoform. The data indicate that expression of MDM2 p90 is regulated through a P53-dependent pathway in response to progesterone.
 ...
PMID:Progesterone inhibition of MDM2 p90 protein in MCF-7 human breast cancer cell line is dependent on p53 levels. 1956 11

MDM2 SNP309 is a single nucleotide T > G polymorphism present in intron 1 of the MDM2 gene. A variety of case-control studies have been published evaluating the association between MDM2 SNP309 and breast cancer risk. However, the published studies, as well as the subsequent meta-analyses, have yielded contradictory results. This meta-analysis aims to examine whether MDM SNP309 polymorphism may exert a differential effect on breast cancer risk along with race. Eligible articles were identified by a search of MEDLINE, Cochrane and EMBASE bibliographical databases for the period July 1993 to June 2009; 16 case-control studies were eligible (12,986 breast cancer cases, 12,993 controls). Subanalyses in case-control studies conducted on Chinese (3 studies, 892 cases, 1,435 controls) and non-Chinese populations (13 studies, 12,094 cases, 11,558 controls) were performed. All pooled odds ratios (ORs) were derived from fixed-effects models given that the between-study heterogeneity was not statistically significant. Subanalysis on Chinese subjects demonstrated that GT and GG genotype were associated with increased breast cancer risk (pooled OR = 1.272, 95% CI 1.025-1.578 and pooled OR = 1.323, 95% CI 1.034-1.694, respectively); as a result the overall effect of the G allele was statistically significant (pooled OR = 1.287, 95% CI 1.048-1.579). On the contrary, no significant associations between MDM2 SNP309 status and breast cancer risk were demonstrated in non-Chinese populations. In conclusion, the association between MDM2 SNP309 and breast cancer is modified by race. MDM2 SNP309 represents a risk factor for breast cancer in Chinese women but not in non-Chinese women. This phenomenon is analogous to that described in the context of lung cancer.
Breast Cancer Res Treat 2010 Feb
PMID:Differential effects of MDM2 SNP309 polymorphism on breast cancer risk along with race: a meta-analysis. 1959 Sep 49

The p53 protein and its regulator MDM2 is central to tumorigenesis by directing cells to undergo cell cycle arrest and/or apoptosis in response to DNA damage or other stress signals. The genes encoding these proteins contain nucleotide variation (p53 codon 72, MDM2 SNP309) that influences cellular response. We examined the p53 codon 72 and MDM2 SNP309 to determine their implication with age of disease onset and risk of breast cancer in young women (<or=36 years). No risk of breast cancer was observed for the genotypes of p53 and MDM2, however, a tendency (P=0.15) towards increased risk of early onset breast cancer was observed in carriers of two or more Pro and/or G alleles. We further calculated the influence on age at diagnosis. Cases were grouped according to the number of G and Pro alleles (0, 1, 2 or 3-4) and age at diagnosis. A significant trend towards decreased age at diagnosis with increased number of risk alleles was found (P=0.013). Our results suggest that p53 codon 72 and MDM2 SNP309 may be implicated in early onset breast cancer.
 ...
PMID:The significance of MDM2 SNP309 and p53 Arg72Pro in young women with breast cancer. 1963 6

We report that amino acids 50 to 77 of azurin (p28) preferentially enter the human breast cancer cell lines MCF-7, ZR-75-1, and T47D through a caveolin-mediated pathway. Although p28 enters p53 wild-type MCF-7 and the isogenic p53 dominant-negative MDD2 breast cancer cell lines, p28 only induces a G(2)-M-phase cell cycle arrest and apoptosis in MCF-7 cells. p28 exerts its antiproliferative activity by reducing proteasomal degradation of p53 through formation of a p28:p53 complex within a hydrophobic DNA-binding domain (amino acids 80-276), increasing p53 levels and DNA-binding activity. Subsequent elevation of the cyclin-dependent kinase inhibitors p21 and p27 reduces cyclin-dependent kinase 2 and cyclin A levels in a time-dependent manner in MCF-7 cells but not in MDD2 cells. These results suggest that p28 and similar peptides that significantly reduce proteasomal degradation of p53 by a MDM2-independent pathway(s) may provide a unique series of cytostatic and cytotoxic (apoptotic) chemotherapeutic agents.
 ...
PMID:A peptide fragment of azurin induces a p53-mediated cell cycle arrest in human breast cancer cells. 1980 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>