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)

17 beta-estradiol induces the synthesis of massive amounts of the hepatic mRNA encoding the Xenopus laevis egg yolk precursor protein, vitellogenin. Vitellogenin mRNA exhibits a half life of approx. 500 h when 17 beta-estradiol is present, and 16 h after removal of 17 beta-estradiol from the culture medium. We recently reported that Xenopus liver contains a protein, which is induced by 17 beta-estradiol and binds with a high degree of specificity to a binding site in a segment of the 3'-untranslated region (3'-UTR) of vitellogenin mRNA implicated in 17 beta-estradiol stabilization of vitellogenin mRNA. To determine if this mRNA binding protein was specific to this system, or if it was present elsewhere, and regulated by other steroids, we examined the tissue distribution and androgen regulation of this protein. Substantial amounts of the vitellogenin 3'-UTR binding protein were found in several Xenopus tissues including testis, ovary and muscle. In the absence of hormone treatment, lung and intestine contained minimal levels of the mRNA binding protein. Testosterone administration induced the vitellogenin 3'-UTR RNA binding protein in several tissues. Additionally, we found a homologous mRNA binding protein in MCF-7, human breast cancer cells. Although the MCF-7 cell protein was not induced by 17 beta-estradiol, the MCF-7 cell mRNA binding protein appears to be closely related to the Xenopus protein since: (i) the human and Xenopus proteins elicit gel shifted bands with the same electrophoretic mobility using the vitellogenin mRNA 3'-UTR binding site; (ii) The human and Xenopus proteins exhibit similar binding specificity for the vitellogenin 3'-UTR RNA binding site; and (iii) RNA from MCF-7 cells is at least as effective as RNA from control male Xenopus liver in blocking the binding of the Xenopus and human proteins to the vitellogenin mRNA 3'-UTR binding site. Its broad tissue distribution and regulation by both 17 beta-estradiol and testosterone suggests that this mRNA binding protein may play a significant role in steroid hormone regulation of mRNA metabolism in many vertebrate cells.
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PMID:Tissue distribution, hormone regulation and evidence for a human homologue of the estrogen-inducible Xenopus laevis vitellogenin mRNA binding protein. 777 54

Thirty-seven families with four or more cases of breast cancer or breast and ovarian cancer were analyzed for mutations in BRCA1. Twelve different germ-line mutations, four novel and eight previously observed, were detected in 16 families. Five families of Ashkenazi Jewish descent carried the 185delAG mutation and shared the same haplotype at eight polymorphic markers spanning approximately 850 kb at BRCA1. Expressivity of 185delAG in these families varied, from early-onset breast cancer without ovarian cancer. Mutation 4184delTCAA occurred independently in two families. In one family, penetrance was complete, with females developing early-onset breast cancer or ovarian cancer and the male carrier developing prostatic cancer, whereas, in the other family, penetrance was incomplete and only breast cancer occurred, diagnosed at ages 38-81 years. Two novel nonsense mutations led to the loss of mutant BRCA1 transcript in families with 10 and 6 cases of early-onset breast cancer and ovarian cancer. A 665-nt segment of the BRCA1 3'-UTR and 1.3 kb of genomic sequence including the putative promoter region were invariant by single-strand conformation analysis in 13 families without coding-sequence mutations. Overall in our series, BRCA1 mutations have been detected in 26 families: 16 with positive BRCA1 lod scores, 7 with negative lod scores (reflecting multiple sporadic breast cancers), and 3 not tested for linkage. Three other families have positive lod scores for linkage to BRCA2, but 13 families without detected BRCA1 mutations have negative lod scores for both BRCA1 and BRCA2.
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PMID:Novel inherited mutations and variable expressivity of BRCA1 alleles, including the founder mutation 185delAG in Ashkenazi Jewish families. 853 57

The evolutionarily conserved prohibitin gene is located on human chromosome 17q21, and two alleles have been identified. Our previous studies characterizing prohibitin in immortalized cells, classified into four complementation groups (A-D) based on the ability of whole-cell hybrids to become senescent, have suggested that it has tumor suppressor activity in group B cells. Only the cell lines assigned to group B are sensitive to the antiproliferative activity of prohibitin, and all are homozygous for an allele designated B because of its exclusive association with this group. Prohibitin genotyping of 22 breast cancer cell lines identified 17 homozygous for the B allele, 5 homozygous for the non-B allele, and no heterozygotes. Four of these cell lines were chosen for further characterization of prohibitin. In cell proliferation assays, the homozygous B breast cancer cell lines (BT-20, SK-BR-3, and MCF7) are all inhibited from traversing the cell cycle following the introduction of wild-type prohibitin transcripts. The cell line homozygous for the alternative non-B allele (BT-549) is not inhibited by transcripts. All of the breast cancer cell lines overexpress the longer form of the prohibitin mRNA (1.9 kb) and the protein. Mutational analysis of the protein-coding region detected no mutations in any of the lines. However, BT-20, SK-BR-3, and MCF7 cells are all mutated in the final 200 bases of the 3' untranslated region (3'UTR) exclusive to the 1.9-kb transcript, but BT-549 cells had no alterations in this region of the 3'UTR. Functional mapping experiments performed in the mutated SK-BR-3 line showed that the wild-type 3'UTR alone is sufficient to inhibit cell cycle progression, indicating that the antiproliferative activity of the prohibitin transcript is localized to this region. Overall, our results show that most (80%) of the cell lines derived from breast tumors have a common prohibitin genotype, suggesting that they belong to the same group of immortalized cells, group B. The results also show that the prohibitin 3'UTR exhibits the characteristics of a trans-acting regulatory RNA (riboregulator), the tumor suppressor activity of which is inactivated by mutation in group B immortalized cells.
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PMID:Prohibitin in breast cancer cell lines: loss of antiproliferative activity is linked to 3' untranslated region mutations. 880 4

In order to evaluate the role of inherited BRCA2 mutations in American families--particularly the appearance in America of European founder mutations--the BRCA2 coding sequence, 5' UTR, and 3' UTR were screened in 22 Caucasian American kindreds with four or more cases of breast or ovarian cancer. Six mutations were found that cause a premature-termination codon; four of them have been reported elsewhere, and two are novel. In the four families with previously seen mutations, the distinct lineages at high risk of cancer were of Dutch, German, Irish, and Ashkenazi Jewish ancestry; mutations in Europe reflect these ancestries. The families with novel mutations were Puerto Rican Hispanic (exon 9 deletion 995delCAAAT) and Ashkenazi Jewish (exon 11 deletion 6425delTT). Among female BRCA2-mutation carriers, risks of breast cancer were 32% by age 50 years, 67% by age 70 years, and 80% by age 90 years, yielding a lifetime risk similar to that for BRCA1 but an older distribution of ages at onset. BRCA2 families also included multiple cases of cancers of the male breast (six cases), ovary (three cases), fallopian tube (two cases), pancreas (three cases), bladder (two cases), and prostate (two cases). Among 17 Ashkenazi Jewish families with four or more breast or ovarian cancers, 9 families (including 3 with ovarian cancer and 1 with male breast cancer) carried none of the three ancient mutations in BRCA1 or BRCA2. To date, both BRCA2 and BRCA1 have been screened by SSCA, supplemented by the protein-truncation test, in 48 families with four or more breast or ovarian cancers. Mutations have been detected in BRCA1 in 33 families, in BRCA2 in 6 families, and in neither gene in 9 families, suggesting both the probable cryptic nature of some mutations and the likelihood of at least one other BRCA gene.
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PMID:BRCA2 in American families with four or more cases of breast or ovarian cancer: recurrent and novel mutations, variable expression, penetrance, and the possibility of families whose cancer is not attributable to BRCA1 or BRCA2. 915 Jan 48

To initiate studies on the transcriptional regulation of the human calcitonin receptor (hCTR) gene, a 4.9-kb hCTR promoter fragment was cloned and hCTR transcriptional initiation sites were mapped in human osteoclasts, kidney, and breast cancer cell line T47D. RT-PCR detected additional hCTR transcripts initiating at least 1 kb 5' to the transcripts mapped above, demonstrating that the hCTR gene is regulated by at least two separate promoters (hCTRP1 and hCTRP2). Transcripts initiating from the upstream promoter (hCTRP2) have a novel 5' untranslated region (5' UTR). Transfection of T47D breast cancer cells with hCTR promoter/luciferase deletion constructs demonstrated that the cloned 4.9-kb hCTR promoter fragment contains both hCTRP1 and hCTRP2 promoters. Fine deletion mapping of the more transcriptionally active hCTRP1 promoter demonstrated that only 97 bp of the hCTRP1 5' flanking region is required for the majority of its transcriptional activity.
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PMID:Multiple promoters regulate human calcitonin receptor gene expression. 1086 Aug 25

We investigated the mechanism of retinoic acid receptor (RAR) beta2 gene silencing in breast cancer cells. Transfection experiments indicated that MCF-7 cells transactivate an exogenous beta2 promoter (-1470/+156) to the same extent as MTSV1.7 breast epithelial cells, which express endogenous RARbeta2. This was true even in the context of replicated chromatin, suggesting a cis-acting rather than a trans-acting defect. Cytosine methylation, a cis-acting DNA modification, has been implicated in RARbeta2 silencing in cancer cells. Upon bisulfite genomic sequencing, we found that 3 CpG sites in the beta2 RARE region were variably methylated in MCF-7 cells but were not methylated in MTSV1.7 cells or in 2 MDA-MB-231 subclones that differed in RARbeta2 expression (high in clone A2, low in clone A4). However, the 5'-UTR region was hypermethylated in clone A4 relative to clone A2 cells. Following 5-azacytidine treatment, RA and trichostatin A markedly induced RARbeta2 expression in MCF-7 cells but not in MDA-MB-231 clone A4 cells. A beta2 RARE reporter construct in which the methylation-susceptible cytosines in the sense strand were replaced by thymine displayed marked loss of activity in a replicated chromatin-dependent manner. We conclude that cytosine methylation contributes to RARbeta2 gene silencing in MCF-7 cells and that methylation of the RARE region may be particularly important. Oncogene (2000) 19, 4066 - 4070.
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PMID:Methylation of conserved CpG sites neighboring the beta retinoic acid response element may mediate retinoic acid receptor beta gene silencing in MCF-7 breast cancer cells. 1096 64

Breast cancer is a heterogeneous disorder in which most tumors display some degree of aneuploidy, especially those at later stages of the disease. Aneuploidy and associated chromosome instability may be important in the progression of mammary tumorigenesis. Aneuploidy is prevented during normal cell division in part through regulation of a mitotic spindle checkpoint where mitotic arrest prevents segregation of misaligned chromosomes into daughter cells at anaphase. Mitotic arrest genes, including the MAD family, which was originally characterized in yeast, help regulate normal function of the mitotic spindle checkpoint. Decreased expression of the human gene MAD2L1 was previously reported in a breast cancer cell line exhibiting chromosome instability and aneuploidy. To explore further the potential role of MAD2L1 in breast cancer, we analyzed MAD2L1 gene expression in 13 minimally to grossly aneuploid human breast cancer cell lines and found significant differences of expression in three lines. Sequence analysis of MAD2L1 cDNA in these as well as nine additional aneuploid breast cancer and five immortalized normal human mammary epithelial cell lines revealed one heterozygous frameshift (572 del A) mutation in a cancer cell line that demonstrated a high level of transcript expression. In addition, two 3'UTR sequence variants were noted in breast cancer cell lines. The 572 del A mutation creates a truncated MAD2 protein product. Further functional studies in primary breast tumors are therefore warranted to determine the potential role MAD2L1 may play in breast cancer.
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PMID:Expression and mutational analyses of the human MAD2L1 gene in breast cancer cells. 1106 82

The epidermal growth factor receptor (EGF-R) plays an important role in the growth and progression of estrogen receptor-negative human breast cancers. EGF binds with high affinity to the EGF-R and activates a variety of second messenger pathways that affect cellular proliferation. However, the underlying mechanisms involved in the regulation of EGF-R expression in breast cancer cells are yet to be described. Here we show that the EGF-induced upregulation of EGF-R mRNA in two human breast cancer cell lines that overexpress EGF-R (MDA-MB-468 and BT-20) is accompanied by stabilization (>2-fold) of EGF-R mRNA. Transient transfections using a luciferase reporter identified a novel EGF-regulated approximately 260-nucleotide (nt) cis-acting element in the 3' untranslated region (3'-UTR) of EGF-R mRNA. This cis element contains two distinct AU-rich sequences (~75 nt), EGF-R1A with two AUUUA pentamers and EGF-R2A with two AUUUUUA extended pentamers. Each independently regulated the mRNA stability of the heterologous reporter. Analysis of mutants of the EGF-R2A AU-rich sequence demonstrated a role for the 3' extended pentamer in regulating basal turnover. RNA gel shift analysis identified cytoplasmic proteins (~55 to 80 kDa) from breast cancer cells that bound specifically to the EGF-R1A and EGF-R2A cis-acting elements and whose binding activity was rapidly downregulated by EGF and phorbol esters. RNA gel shift analysis of EGF-R2A mutants identified a role for the 3' extended AU pentamer, but not the 5' extended pentamer, in binding proteins. These EGF-R mRNA-binding proteins were present in multiple human breast and prostate cancer cell lines. In summary, these data demonstrate a central role for mRNA stabilization in the control of EGF-R gene expression in breast cancer cells. EGF-R mRNA contains a novel complex AU-rich 260-nt cis-acting destabilizing element in the 3'-UTR that is bound by specific and EGF-regulated trans-acting factors. Furthermore, the 3' extended AU pentamer of EGF-R2A plays a central role in regulating EGF-R mRNA stability and the binding of specific RNA-binding proteins. These findings suggest that regulated RNA-protein interactions involving this novel cis-acting element will be a major determinant of EGF-R mRNA stability.
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PMID:Identification of a novel AU-Rich element in the 3' untranslated region of epidermal growth factor receptor mRNA that is the target for regulated RNA-binding proteins. 1123 42

The enzyme human steroid 5-alpha reductase type II (SRD5A2) and androgen receptor (AR) are critical mediators of androgen action, suggesting a potential role in hormonally related cancers. The SRD5A2 gene harbours two frequent polymorphic sites, one in the coding region, at codon 89 of exon 1, where valine is substituted by leucine (V89L) and the other in the 3' untranslated region (3' UTR) where a variable number of dinucleotide TA repeat lengths exists. The V89L polymorphism is known to alter the activity of this enzyme. In the present study we examined 144 sporadic breast tumours from Italian patients for the V89L and TA polymorphisms by sequence and fragment analysis, respectively. Tumour extract prostate specific antigen (PSA) concentration as well as a number of well-established clinical and pathological parameters were evaluated. The results show that 53% of the tumours were homozygous for VV alleles, 37% were heterozygous for VL alleles and 10% were homozygous for LL alleles. TA(0) repeats were found in tumours with VV, LL and VL genotypes. TA(9) repeats were only found in VV homozygotes and were totally absent from either LL homozygotes or VL heterozygotes. PSA expression was significantly elevated in tumours with VV genotype. The presence of LL alleles in breast tumours is associated with earlier onset and shorter disease-free (RR = 2.65;P = 0.013) and overall survival (RR = 3.06;P = 0.014) rates. The VV genotype is associated with a more favourable prognosis. Our study suggests that the polymorphism in codon 89 of exon 1 of the human 5 alpha-reductase gene is related with TA repeat genotypes, PSA expression and breast cancer prognosis. More specifically, we found that the LL genotype is also associated with earlier onset and more aggressive forms of breast cancer. Long-term-outcome studies are needed to investigate the relevance of this polymorphism to breast cancer susceptibility.
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PMID:Codon 89 polymorphism in the human 5 alpha-reductase gene in primary breast cancer. 1125 89

In order to detect the contribution of cytochrome P450 1A1 (CYP1A1), aryl hydrocarbon receptor (AhR), glutathione S-transferases M1 (GSTM1), P1 (GSTP1), and T1 (GSTT1) genes in breast cancer, genetic analysis was performed, as well as transcriptional analysis in sporadic primary tumours and corresponding adjacent normal tissues from the same patient. CYP1A1 3'-untranslated region (3'-UTR) termed as m1 (MspI) polymorphism and the null(-) deletions of both GSTM1 and GSTT1 genes were examined in genomic DNA from blood samples of 207 female breast cancer patients and 171 age and sex matched controls. The frequencies of the m1 genotype of the CYP1A1 gene in cases and controls were 0.13 and 0.15, while the frequencies of homozygotes with GSTM1(-) were 0.52, in each, and for homozygotes with GSTT1(-) were 0.14 and 0.10, respectively. Statistical analysis of these genotypes in combinations did not reveal any significant difference between the breast cancer population and the control group. Expression of mRNA levels of CYP1A1, GSTM1, GSTP1, GSTT1 and AhR genes in 31 breast cancer patients, revealed inter-individual variation in an independent manner to patient age, genotype, or tumour stage. Eighty-seven percent of the tumour specimens tested were deregulated, compared to their normal counterparts, in at least one locus. Up-regulation of CYP1A1 was observed only when one of the GSTM1 or GSTP1 was down-regulated while the other remained constant. Genotyping analysis did not show any correlation to breast cancer risk. However, RT-PCR analysis provided evidence that CYP1A1, AhR, GSTM1, GSTP1 and GSTT1 genes are frequently deregulated in breast cancer and could be used as molecular biomarkers for better clinical management of such patients, with respect to chemotherapy.
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PMID:Genetic polymorphisms and transcriptional pattern analysis of CYP1A1, AhR, GSTM1, GSTP1 and GSTT1 genes in breast cancer. 1140 54


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