Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

GATA binding protein 3 (GATA3) is a transcriptional activator highly expressed by the luminal epithelial cells in the breast. Here we did a meta-analysis of the available breast cancer cDNA data sets on a cohort of 305 patients and found that GATA3 was one of the top genes with low expression in invasive carcinomas with poor clinical outcome. To validate its prognostic utility, we did a tissue microarray analysis on a cohort of 139 consecutive invasive carcinomas (n = 417 tissue samples) immunostained with a monoclonal antibody against GATA3. Low GATA3 expression was associated with higher histologic grade (P < 0.001), positive nodes (P = 0.002), larger tumor size (P = 0.03), negative estrogen receptor and progesterone receptor (P < 0.001 for both), and HER2-neu overexpression (P = 0.03). Patients whose tumors expressed low GATA3 had significantly shorter overall and disease-free survival when compared with those whose tumors had high GATA3 levels. The hazard ratio of metastasis or recurrence according to the GATA3 status was 0.31 (95% confidence interval, 0.13-0.74; P = 0.009). Cox multivariate analysis showed that GATA3 had independent prognostic significance above and beyond conventional variables. Our data suggest that immunohistochemical analysis of GATA3 may be the basis for a new clinically applicable test to predict tumor recurrence early in the progression of breast cancer.
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PMID:Identification of GATA3 as a breast cancer prognostic marker by global gene expression meta-analysis. 1635 29

In human breast cancer, estrogen receptor-alpha (ERalpha), progesterone receptor (PR) and human epidermal growth factor receptor (ERBB2) status are currently determined using different techniques. We propose to assess the mRNA expression of these three clinically relevant markers using a unique technique, real-time nucleic acid sequence-based amplification (NASBA). Gene expression of hormone receptors was analyzed and compared to the cytosolic functional protein content as determined with a ligand binding assay (LBA), while ERBB2 mRNA expression was compared to quantitative PCR and ELISA. We observed that the three markers are significantly overexpressed at the mRNA level in positive tumors, as measured by DNA- or protein-based techniques. Biostatistical analysis of the receiver operating characteristic (ROC) curve demonstrated high concordance between NASBA and LBA [area under the curve (AUC) for ROC of 0.899] and showed that ERalpha status could be predicted using the molecular assay with a sensitivity of 72.7% and a specificity of 93.5%. Similar results were obtained for PR (AUC ROC 0.938, sensitivity 75.3%, specificity 100%). Moreover, excellent concordance was observed between NASBA, quantitative PCR and ELISA with respect to ERBB2 (AUC ROC 0.92, sensitivity 90%, specificity 89.7%; and AUC ROC 0.98, sensitivity 100%, specificity 91.5%, respectively). These results suggest that NASBA is well suited for assessing ER, PR and ERBB2 status in breast tumor samples. This approach is rapid, highly sensitive and a standardized method that could be complementary to the existing techniques, especially for small tumors.
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PMID:NASBA: a novel approach to assess hormonal receptors and ERBB2 status in breast cancer. 1637 77

We investigated estrogen-like properties of five perfluorinated compounds using a combination of three in vitro assays. By means of an E-screen assay, we detected the proliferation-promoting capacity of the fluorotelomer alcohols 1H,1H,2H,2H-perfluorooctan-1-ol (6:2 FTOH) and 1H,1H,2H,2H-perfluoro-decan-1-ol (8:2 FTOH). The more widely environmentally distributed compounds perfluoro-1-octane sulfonate, perfluorooctanoic acid, and perfluorononanoic acid did not seem to possess this hormone-dependent proliferation capacity. We investigated cell cycle dynamics using flow cytometric analyses of the DNA content of the nuclei of MCF-7 breast cancer cells. Exposure to both fluorotelomer alcohols stimulated resting MCF-7 cells to reenter the synthesis phase (S-phase) of the cell cycle. After only 24 hr of treatment, we observed significant increases in the percentage of cells in the S-phase. In order to further investigate the resemblance of the newly detected xenoestrogens to the reference compound 17beta-estradiol (E2), gene expression of a number of estrogen-responsive genes was analyzed by real-time polymerase chain reaction. With E2, as well as 4-nonylphenol and the fluorotelomer alcohols, we observed up-regulation of trefoil factor 1, progesterone receptor, and PDZK1 and down-regulation of ERBB2 gene expression. We observed small but relevant up-regulation of the estrogen receptor as a consequence of exposures to 6:2 FTOH or 8:2 FTOH. The latter finding suggests an alternative mode of action of the fluorotelomer alcohols compared with that of E2. This study clearly underlines the need for future in vivo testing for specific endocrine-related end points.
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PMID:Estrogen-like properties of fluorotelomer alcohols as revealed by mcf-7 breast cancer cell proliferation. 1639 65

ERBB2 (HER2/Neu) gene amplification and overexpression is associated with increased risk of metastases and shorter survival in breast cancer. Tyrosine 1248 is a major phosphorylation site of ERBB2 and reflects the activation status of the receptor. The aim of this study was to investigate the relationships between quantitative levels of pY1248-ERBB2 (p-ERBB2) and the expression of epidermal growth factor receptor (EGFR)-family members, and whether p-ERBB2 could provide additional prognostic value compared with established prognostic markers. For this purpose we developed a highly sensitive chemiluminescence-linked immunoassay (CLISA) and detected p-ERBB2 levels in 70 primary breast cancer biopsies. Phosphorylated ERBB2 correlated with EGFR and ERBB2, and inversely with oestrogen receptor (ER), progesterone receptor (PgR) and ERBB4 expression levels. Additionally, p-ERBB2 was associated with poor clinical outcome in univariate and multivariate Cox regression analysis. Further studies are needed to evaluate the predictive value of p-ERBB2.
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PMID:Phosphorylation of tyrosine 1248-ERBB2 measured by chemiluminescence-linked immunoassay is an independent predictor of poor prognosis in primary breast cancer patients. 1641 59

The proto-oncogene c-KIT (CD117) is highly expressed in normal breast epithelium and is decreased in invasive breast cancer. In this study, we analyzed the protein expression and the mutational status of c-KIT in ductal carcinoma in situ (DCIS) of the breast and correlated these findings with nuclear grade, architectural pattern, and expression of HER-2, estrogen receptor (ER)-alpha, and progesterone receptor (PR). C-KIT, HER-2, ER, and PR expression were analyzed immunohistochemically in 106 cases of paraffin-embedded DCIS (85 pure DCIS and 21 DCIS with concurrent carcinoma). Direct sequencing of exons 9 and 11 of the c-KIT gene was performed to analyze the hot spot mutational regions in representative cases. C-KIT expression was found in 55 (52.8%) of all DCIS, correlating with high nuclear grade (P < .0001), comedonecrosis (P < .0001), and solid growth pattern (P = .001). Furthermore, c-KIT expression was strongly associated with HER-2 positivity (P < .0001) and was significantly lower in ER- or PR-positive cases (P = .001 and P = .006, respectively). C-KIT expression alone or co-expression with HER-2 in pure DCIS did not differ significantly from DCIS with invasive component (P = .09). Mutational analysis in 6 c-KIT-positive DCIS revealed no activating mutations in exons 9 or 11. Our findings suggest that the expression of c-KIT protein might define a subset of poorly differentiated, HER-2-positive DCIS with decreased expression of steroid hormone receptors, comedonecrosis, and a solid growth pattern. The implications of c-KIT and HER-2 co-expression for breast carcinogenesis should be further evaluated.
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PMID:C-KIT expression in ductal carcinoma in situ of the breast: co-expression with HER-2/neu. 1642 21

Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. It was originally hypothesized that the ability of PR to predict response to endocrine therapy was due to the fact that PR is an estrogen-regulated gene and that its levels represented a marker of functional ER activity. However, it is now known that loss of PR can occur via multiple mechanisms, many of which do not include ER function, e.g., hypermethylation of the PR promoter and loss of heterozygosity of the PR gene. We have shown that growth factor signaling pathways can directly down-regulate PR levels via the phosphatidylinositol 3'-kinase (PI3K)/Akt/mTOR pathway, and that this can occur independent of ER. For example, overexpression of myr-Akt in MCF-7 cells causes complete loss of PR protein and mRNA but does not reduce ER levels or activity, thus generating ER+/PR- MCF-7 cells. Therefore, the absence of PR may not simply reflect a lack of ER activity but rather may reflect hyperactive cross-talk between ER and growth factor signaling pathways. Consistent with this hypothesis, several recent clinical studies have found that ER+/PR- breast cancers overexpress human epidermal growth factor receptor (HER) 1 and HER2 compared with ER+/PR+ breast cancers. Although HER receptors can lower ER levels, one study showed that loss of PR correlated with high HER2 levels in a multivariate analysis. Furthermore, loss of PTEN, a negative regulator of the PI3K/Akt signaling pathway, has been shown to be associated with specific loss of PR and no change in ER levels. Given the well-recognized resistance of ER+/PR- breast cancer to antiestrogens, more studies are needed to better understand the etiology of ER+/PR- breast cancer, particularly the analysis of other growth factor receptors and their downstream signaling intermediates with respect to PR status.
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PMID:Progesterone receptor loss correlates with human epidermal growth factor receptor 2 overexpression in estrogen receptor-positive breast cancer. 1646 18

Taking a series of repeat biopsies or fine needle aspirates of a tumor during the course of therapy can provide information about treatment-induced changes in tumor biomarkers and help monitor patient response to adjuvant therapy. It is hoped that analysis of biomarkers in serial biopsies will also further our understanding of the molecular mechanisms that determine a tumor's response or resistance to therapy, may facilitate investigation of molecular biology of tumor response, and may provide useful information informing the development of new drugs for breast cancer therapy. In this chapter, practical, clinical considerations in the taking of repeat biopsies are considered and protocols for the taking of fine needle aspirates and core-cut/trucut biopsies are detailed. Their assessment for biomarkers indicative of cellular proliferation, apoptosis, and endocrine response/resistance such as estrogen and progesterone receptor status, HER2 and epidermal growth factor receptor are considered.
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PMID:Serial biopsies/fine-needle aspirates and their assessment. 1649 90

Glycogen-rich clear cell carcinoma (GRCC) of the breast is a rare variant of primary breast carcinoma that was first described by Hull et al. in 1981, and is characterized by carcinoma cells containing an optically clear cytoplasm and intracytoplasmic glycogen. The present case involved a 33-year-old female. She had noticed a lump in the inner quadrant of the left breast. The tumor obtained by enucleation biopsy had an irregular shape. The tumor cells exhibited sharply defined borders, polygonal contours, a clear or finely granular cytoplasm, and moderate nuclear atypia. The tumor cells showed a positive reaction with periodic acid Schiff, eliminated by diastase digestion. The tumor was diagnosed as GRCC. There was no nodal metastasis. Immunohistochemically, the tumor cells were positive for cytokeratin, epithelial membrane antigen, HER2, and p53, but negative for estrogen receptor (ER) and progesterone receptor (PR). Although the biological behavior of GRCC is difficult to predict in view of the very limited number of case reports, the prognosis of GRCC may be associated with not only histopathological subtype but also other clinicopathological factors, such as size, status of invasion, status of nodal metastasis, nuclear grade, ER, PR, HER-2, p53 and so on. To clarify the pathogenesis of mammary GRCC, the systematic study of additional well-documented cases with long-term follow up will be necessary.
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PMID:Histopathological and immunohistochemical findings in a case of glycogen-rich clear cell carcinoma of the breast. 1649 26

Basal-like carcinomas have recently been identified in gene expression profiling studies as a subtype of invasive breast cancer. These lesions are estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative (triple negative), and typically express basal cytokeratins, epidermal growth factor receptor (EGFR), and/or c-kit. As poorly differentiated invasive ductal carcinomas, they presumably have a ductal carcinoma in situ (DCIS) precursor with similar cytologic and immunophenotypic features. However, the frequency and even the existence of a DCIS lesion with an immunophenotype analogous to that of invasive basal-like carcinomas have not been previously evaluated. We studied 66 cases of high nuclear grade DCIS using antibodies to ER, PR, HER2, three basal cytokeratins, EGFR, and c-kit to determine the frequency of the triple negative phenotype, and to determine the relationship between the triple negative phenotype and expression of basal cytokeratins and other biomarkers characteristically expressed by invasive basal-like carcinomas. Four cases (6%) exhibited the triple negative phenotype; the remaining cases showed other combinations of ER, PR, and HER2 expression (nontriple negative). Basal cytokeratins, EGFR, or both were expressed by all four triple negative lesions, but by only 21 of 51 (42%) nontriple negative cases (P = 0.04). We conclude that a small proportion of high-grade ductal carcinomas in situ exhibit an ER-negative/PR-negative/HER2-negative (triple negative) phenotype, and these lesions more commonly show expression of basal cytokeratins and/or EGFR than nontriple negative high-grade DCIS. Given that invasive breast cancers typically share immunophenotypic features with the ductal carcinoma in situ from which they arise, our findings raise the possibility that the triple-negative, basal cytokeratin and/or EGFR-positive DCIS lesions we identified represent a precursor lesion to invasive basal-like carcinomas.
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PMID:Ductal carcinoma in situ with basal-like phenotype: a possible precursor to invasive basal-like breast cancer. 1652 77

Breast cancer is a hormone-dependent cancer, and the presence of estrogen receptor (ER) and progesterone receptor (PgR) in tumors is used clinically to predict the likelihood of response to hormonal therapies. This review describes the roles of (1) hormone related factors (ER, PgR, phosphorylated ER, ERbeta, aromatase), (2) growth related factors (HER2, Ki67, p53), (3) ER cofactors (AIB1, NcoR1), (4) estrogen dependent genes derived from gene expression profiling (HDAC6, IGFBP4/5), and (5) gene profiling using cDNA microarray. There are, however, considerable methodological difficulties in identifying useful predictive factors but on the basis of current evidence other biomarkers add little additional information. The prospective and multi-centered analyses will be warranted to develop the predictive factors for directing use of these therapies.
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PMID:[Predictive factors of hormonal therapy in breast cancer]. 1652 49


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