Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
 95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the past decade, progress in endocrine therapy and the use of trastuzumab has significantly contributed to the decline in breast cancer mortality for hormone receptor-positive and ERBB2 (HER2)-positive cases, respectively. As a result of these advances, a breast cancer cluster with poor prognosis that is negative for the estrogen receptor (ESR1), the progesterone receptor (PRGR) and ERBB2 (triple negative) has come to the forefront of medical therapeutic attention. DNA microarray analyses have revealed that this cluster is phenotypically most like the basal-like breast cancer that is caused by deficiencies in the BRCA1 pathways. To gain further improvements in breast cancer survival, new types of drugs might be required, and small molecules targeting the ubiquitin proteasome system have moved into the spotlight. The success of bortezomib in the treatment of multiple myeloma has sent encouraging signals that proteasome inhibitors could be used to treat other types of cancers. In addition, ubiquitin E3s involved in ESR1, ERBB2 or BRCA1 pathways could be ideal targets for therapeutic intervention. This review summarizes the ubiquitin proteasome pathways related to these proteins and discusses the possibility of new drugs for the treatment of breast cancers. PUBLICATION HISTORY : Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
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PMID:The UPS: a promising target for breast cancer treatment. 1900 32

The pathogenesis of late normal tissue fibrosis after high-dose ionizing radiation involves multiple cell types and signalling pathways but is not well understood. To identify the molecular changes occurring after radiotherapy, paired normal tissue samples were collected from the non-irradiated breast and from the treated breast of women who had undergone curative radiotherapy for early breast cancer months or years previously. As radiation may induce distinct transcriptional changes in the different components of the breast, laser capture microdissection and gene expression microarray profiling were performed separately for epithelial and stromal components and selected genes were validated using immunohistochemistry. In the epithelial compartment, a reduction of KIT (c-Kit; CD117) and a reciprocal increase in ESR1 (oestrogen receptor-alpha, ERalpha) mRNA and protein levels were seen in irradiated compared to non-irradiated samples. In the stromal compartment, extracellular matrix genes including FN1 (fibronectin 1) and CTGF (connective tissue growth factor; CCN2) were increased. Further investigation revealed that c-Kit and ERalpha were expressed in distinct subpopulations of luminal epithelial cells. Interlobular c-Kit-positive mast cells were also increased in irradiated cases not showing features of post-radiation atrophy. Pathway analysis revealed 'cancer, reproductive system disease and tumour morphology' as the most significantly enriched network in the epithelial compartment, whereas in the stromal component, a significant enrichment for 'connective tissue disorders, dermatological diseases and conditions, genetic disorder' and 'cancer, tumour morphology, infection mechanism' networks was observed. These data identify previously unreported changes in the epithelial compartment and show altered expression of genes implicated in late normal tissue injury in the stromal compartment of normal breast tissue. The findings are relevant to both fibrosis and atrophy occurring after radiotherapy for early breast cancer.
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PMID:Genome-wide transcriptomic profiling of microdissected human breast tissue reveals differential expression of KIT (c-Kit, CD117) and oestrogen receptor-alpha (ERalpha) in response to therapeutic radiation. 1956 35

We evaluated the association of epidermal growth factor receptor (EGFR) 142285G>A (R521K) and estrogen receptor alpha (ESR1) 2014G>A (T594T) single nucleotide polymorphisms with breast cancer risk and prognosis in Tunisian patients. EGFR 142285G>A and ESR1 2014G>A were genotyped in a sample of 148 Tunisian breast cancer patients and 303 controls using PCR-RFLP method. Immunohistochemitsry was used to evaluate the expression levels of EGFR, HER2, ESR1, progesterone receptor and BCL2 in tumors. We found no evidence for an association between EGFR R521K polymorphism and breast cancer risk. However, we found that the homozygous GG (Arg) genotype was more prevalent in patients with lymph node metastasis (P = .03) and high grade tumors (P = .011). The ESR1 2014G allele showed significant association with breast cancer risk (P = .025). The GG genotype was associated with HER2 overexpression and this association withstood univariate and multivariate analyses (P = .009; P = .021, resp.). These data suggest that the R521K might be a prognostic factor, because it correlates with both tumor grade and nodule status. The higher expression of HER2 in ESR1 T594T GG patients suggests the possibility that ESR1 gene polymorphisms accompanied by HER2 expression might influence the pathogenesis of breast cancers.
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PMID:Genetic polymorphisms in the EGFR (R521K) and estrogen receptor (T594T) genes, EGFR and ErbB-2 protein expression, and breast cancer risk in Tunisia. 1963 71

We aimed to determine changes in the expression of the genes CDH1, CDH13, CD44, and TIMP3 to look for any relationship between them, HER2 and ESR1 expression at the RNA level, and the histopathological properties of tumors. We also analyzed the expression properties of double-negative (estrogen receptor [ER] and human epidermal growth factor receptor [HER2] both negative) breast tumors. Expression status was studied in fresh tissue at the mRNA level with quantitative PCR using hydrolysis probes. Sixty-two cancer patients and four normal controls were included in the study. When the tumor group was analyzed as a whole, the correlations of ESR1 with CDH1, CDH13, and TIMP3 were P < 0.05, P < 0.005, and P < 0.005, respectively. In ER-positive tumors, CDH1 and CDH13 were correlated directly (P < 0.005) when HER2 was correlated with CDH1, CDH13, and TIMP3 indirectly (P < 0.005, P < 0.005, and P < 0.05, respectively). CDH1 and CD44 had a strong indirect correlation (P < 0.005) in ER-negative tumors. There were significant differences in the expression levels of the CDH13, TIMP3, and CD44 genes (P < 0.005, P < 0.005, and P < 0.05, respectively) between the ER-positive and -negative groups. All four genes were found to be correlated with invasive properties in both ER-positive and -negative tumors. In double-negative tumor samples, only CD44 had a significant and strong correlation with stage, lymph node involvement, and metastasis (P < 0.05, P < 0.005, and P < 0.05, respectively). As a conclusion, a decrease in CDH1, CDH13, and TIMP3 expression levels with an increase in CD44 can be used as an indicator for invasion in both ER-positive and -negative breast tumors. In double-negative tumor tissues, CD44 can be considered a marker for aggressive properties.
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PMID:Predicting invasive phenotype with CDH1, CDH13, CD44, and TIMP3 gene expression in primary breast cancer. 1979 9

Many studies correlating gene expression data to clinical parameters assume a linear increase or decrease of the clinical parameter under investigation with the expression of a gene. We have studied genes encoding important breast cancer-related proteins using a model for survival-type data that is based on natural splines and the Cox proportional hazard model, thereby removing the linearity assumption. Expression data of 16 genes were studied in relation to metastasis-free probability in a cohort of 295 consecutive breast cancer patients treated at The Netherlands Cancer Institute. The independent predictive power for disease outcome of the 16 individual genes was tested in a multivariable model with known clinical and pathological risk factors. There is a linear relationship between increasing expression and a higher or lower hazard for distant metastasis for ESR1, ERBB4, VEGF, CCNE2, EZH2, and UPA; for ERBB2, ERBB3, CCND1, CCNE1, EED, CXCR4, CCR7, SDF1, and PAI1 there is no clear increase or decrease; and for EGFR there seems to be a non-linear relation. Multivariable analysis showed that the 70-gene prognosis profile outperforms all the other variables in the model (hazard-rate 5.4, 95% CI 2.5-11.7; P = 0.000018). EGFR-expression seems to have a non-linear relation with disease outcome, indicating that lower but also higher expression of EGFR are associated with worse outcome compared to intermediate expression levels; the other genes show no or a linear relation.
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PMID:Analysis of breast cancer related gene expression using natural splines and the Cox proportional hazard model to identify prognostic associations. 1985 4

Cell division cycle 7 is a widely expressed protein kinase implicated in cell division, cell cycle checkpoint mechanisms, and cancer progression. To determine the relationship of cell division cycle 7 protein expression with tumor phenotype, molecular features and prognosis, 2197 highly characterized breast carcinomas were analyzed on a tissue microarray. Detectable cell division cycle 7 expression was found in 1088 (57%) of breast cancer specimens and 228 (11.9%) exhibited a moderate or strong expression. High levels of cell division cycle 7 expression were significantly related to medullary histotype (P < .0001); high tumor grade (P < .0001); negative estrogen receptor status (P < .0001); high Ki67 expression level (P < .0001); p53 and p16 overexpression (P < .0001); and amplification of HER2 (P < .0001), c-myc (P < .0001), MDM2 (P = .043), CCND1 (P = .0084), and ESR1 (P = .0012) as well as with the number of amplified genes (P < .0001). There was also a tendency towards worse prognosis in cell division cycle 7 positive as compared to negative breast cancers. The relationship between cell division cycle 7 and number of amplifications was independent from tumor proliferation raising the possibility of a direct influence of cell division cycle 7 expression for amplification development. In conclusion, cell division cycle 7 is a replication associated protein with relationships to gene amplification and genomic instability in breast carcinomas. These data support the potential utility of newly developed small molecule cell division cycle 7 inhibitors as a therapeutic alternative in at least a subset of breast carcinomas.
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PMID:Overexpression of cell division cycle 7 homolog is associated with gene amplification frequency in breast cancer. 1989 97

Multiple different biologically and clinically relevant genes are often amplified in invasive breast cancer, including HER2, ESR1, CCND1, and MYC. So far, little is known about their role in tumor progression. To investigate their significance for tumor invasion, we compared pure ductal carcinoma in situ (DCIS) and DCIS associated with invasive cancer with regard to the amplification of these genes. Fluorescence in situ hybridization (FISH) was performed on a tissue microarray containing samples from 130 pure DCIS and 159 DCIS associated with invasive breast cancer. Of the latter patients, we analyzed the intraductal and invasive components separately. In addition, lymph node metastases of 23 patients with invasive carcinoma were included. Amplification rates of pure DCIS and DCIS associated with invasive cancer did not differ significantly (pure DCIS vs. DCIS associated with invasive cancer: HER2 22.7 vs. 24.2%, ESR1 19.0 vs. 24.1%, CCND1 10.0 vs. 14.8%, MYC 11.8 vs. 6.5%; P > 0.05). Furthermore, we observed a high concordance of the amplification status for all genes if in situ and invasive carcinoma of individual patients were compared. This applied also to the corresponding lymph node metastases. Our results indicate no significant differences between the gene amplification status of DCIS and invasive breast cancer concerning HER2, ESR1, CCND1, and MYC. Therefore, our data suggest an early role of all analyzed gene amplifications in breast cancer development but not in the initiation of invasive tumor growth.
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PMID:Gene amplification in ductal carcinoma in situ of the breast. 2003 84

Epidemiologic studies have established that pregnancy has a bidirectional, time-dependent effect on breast cancer risk; a period of elevated risk is followed by a long-term period of protection. The purpose of the present study was to determine whether pregnancy and involution are associated with gene expression changes in the normal breast, and whether such changes are transient or persistent. We examined the expression of a customized gene set in normal breast tissue from nulliparous, recently pregnant (0-2 years since pregnancy), and distantly pregnant (5-10 years since pregnancy) age-matched premenopausal women. This gene set included breast cancer biomarkers and genes related to immune/inflammation, extracellular matrix remodeling, angiogenesis, and hormone signaling. Laser capture microdissection and RNA extraction were done from formalin-fixed paraffin-embedded reduction mammoplasty and benign biopsy specimens and analyzed using real-time PCR arrays containing 59 pathway-specific and 5 housekeeping genes. We report 14 of 64 (22%) of the selected gene set to be differentially regulated (at P < 0.05 level) in nulliparous versus parous breast tissues. Based on gene set analysis, inflammation-associated genes were significantly upregulated as a group in both parous groups compared with nulliparous women (P = 0.03). Moreover, parous subjects had significantly reduced expression of estrogen receptor alpha (ERalpha, ESR1), progesterone receptor (PGR), and ERBB2 (Her2/neu) and 2-fold higher estrogen receptor-beta (ESR2) expression compared with nulliparous subjects. These initial data, among the first on gene expression in samples of normal human breast, provide intriguing clues about the mechanisms behind the time-dependent effects of pregnancy on breast cancer risk.
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PMID:Gene expression patterns in the human breast after pregnancy. 2017 93

Polymorphisms in estrogen receptor alpha gene (ESR1) have been previously associated with breast cancer risk; however, the results were not fully consistent. Our purpose was to study interactions between common genotypes in ESR1, breast cancer risk and tumor phenotypes. 6 ESR1 single nucleotide polymorphisms (SNPs) were genotyped in 103 breast cancer patients and 90 controls using hybridization probes; the genotypes were correlated with known prognostic factors for breast cancer and 5 years-follow up data. To assess estrogen and progesterone receptors (ER, PR) and HER2/neu expressions, immunohistochemistry was performed. Our results showed that rs3798577 was significantly associated with the risk of breast cancer, the common allele C conferring susceptibility (p-trend=4 x 10(-5)); rs3798577 was also correlated with PR expression (p=0.01), but not with ER expression; rs2228480 (p=0.047) and rs1801132 (p=0.02) were associated with the age at diagnosis; rs1801132 was correlated with hypercholesterolemia (p=0.003) and increased BMI (body mass index) (p=0.01); rs2234693 showed a low significant association (p=0.042) with the tumor grade; rs3798577 was correlated with disease-free survival (p=0.05), allele C conferring increased risk for relapses, but it reached not statistical significance after adjustments. In conclusions, we identified four genotypes significantly correlated with either the risk or some tumor characteristics, suggesting that the main selection criteria of the investigated SNPs (frequency and the position in modulating domains of the gene) are pertinent instruments for establish correlations between the gene structure and the tumor phenotype.
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PMID:Estrogen receptor alpha polymorphisms: correlation with clinicopathological parameters in breast cancer. 2042 21

Several oncogenes and tumor-suppressor genes have been shown to be implicated in the development, progression and response to therapy of invasive breast cancer. The phenotypic uniqueness (and thus the heterogeneity of clinical behavior) among patients' tumors may be traceable to the underlying variation in gene copy number of these genes. To obtain a more complete view of gene copy number changes and their relation to phenotype, we analyzed 20 breast cancer-related genes in 104 invasive breast cancers with the use of multiplex ligation-dependent probe amplification (MLPA). We identified MYC gene amplification in 48% of patients, PRDM14 in 34%, topoisomerase IIalpha (TOP2A) in 32%, ADAM9 in 32%, HER2 in 28%, cyclin D1 (CCND1) in 26%, EMSY in 25%, IKBKB in 21%, AURKA in 17%, FGFR1 in 17%, estrogen receptor alpha (ESR1) in 16%, CCNE1 in 12% and EGFR in 9% of patients. There was a significant correlation between the number of amplified genes and the histological grade and mitotic index of the tumor. Gene amplifications of EGFR, CCNE1 and HER2 were negatively associated with estrogen receptor status whereas FGFR1, ADAM9, IKBKB and TOP2A revealed a positive association. Amplifications of ESR1, PRDM14, MYC and HER2 were associated with a high mitotic index, and PRDM14 and HER2 amplifications with high histological grade. MYC amplification was detected more frequently in ductal tumors and high-level MYC amplifications were significantly associated with large tumor size. HER2/MYC, HER2/CCNE1 and EGFR/MYC co-amplified tumors were significantly larger than tumors with either of these amplifications. Gene loss occurred most frequently in E-cadherin (CDH1) (20%) and FGFR1 (10%). In conclusion, MLPA analysis with this 'breast cancer kit' allowed to simultaneously assess copy numbers of 20 important breast cancer genes, providing an overview of the most frequent (co)amplifications as well as interesting phenotypic correlations, and thereby data on the potential importance of these genes in breast cancer.
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PMID:Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes. 2047 80


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