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)

The selection of a systemic breast cancer therapy is based on the expression pattern of immunohistochemical prognostic markers. In our study we sought to determine whether neoadjuvant chemotherapy may alter these expression patterns within the tumors. Our hypothesis was that the expression of the immunohistochemical prognostic markers does not differ between tissue specimens before and after neoadjuvant chemotherapy. We determined the protein expression levels of estrogen receptor, progesterone receptor, Ki67, p53 and HER2/neu in the core biopsy and the resected tumor sample from 25 patients receiving neoadjuvant chemotherapy. As a control group, we analyzed sample pairs from 30 patients who did not receive neoadjuvant chemotherapy. Additionally, we determined the relative HER2/neu gene copy number by FISH and/or real-time PCR. There were no significant differences in the changes in expression patterns from the core biopsy to the treated resected tumor between those who had received neoadjuvant chemotherapy and the control group. We suggest that it is sufficient to analyze the prognostic factors from either the core biopsy prior to chemotherapy or the treated tumor sample instead of investigating both samples. This would markedly reduce the costs.
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PMID:HER2/neu, p53, Ki67, and hormone receptors do not change during neoadjuvant chemotherapy in breast cancer. 1583 46

Meningothelial hyperplasia is a poorly characterized entity, often associated with advanced age, chronic renal failure, trauma, hemorrhage, and neoplasia. In order to elucidate the nature of this lesion, 11 cases defined by the presence of nests of 10 or more cell layers thick, were compared with normal arachnoidal cap cells and meningiomas. Immunohistochemistry and FISH were performed to determine NF2 (merlin), protein 4.1B, EMA, progesterone receptor (PR), EGFR, survivin, VEGF, PDGF-BB, PDGFR-beta, E-cadherin, and cathepsin D status. All cases had at least one putative predisposing factor, including hemorrhage (7), chronic renal disease (5), old age (5), trauma (1), and an adjacent optic nerve pilocytic astrocytoma (1). There was typically a discontinuous growth pattern, with no invasion of surrounding normal tissue. No gene deletions were found, though scattered polyploid cells were seen in 2 cases. The immunoprofile was similar to normal cap cells with one exception; whereas normal cells were uniformly negative for PR, nuclear positivity was seen in 64% of hyperplasias, a frequency similar to that of benign meningiomas. Our data suggest that meningothelial hyperplasia is a reactive process that is usually distinguishable from meningioma based on clinicopathologic and genetic features. It may be preneoplastic in some, though further studies are needed to test this hypothesis.
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PMID:Meningothelial hyperplasia: a detailed clinicopathologic, immunohistochemical and genetic study of 11 cases. 1591 82

Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of high-grade, highly proliferating, estrogen receptor- and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor- and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma.
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PMID:The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications. 1593 54

Meningiomas are histologically and clinically diverse CNS neoplasms with few available immunohistochemical markers of differentiation and progression. Therefore, we investigated a panel of potentially useful meningioma-associated biomarkers using high throughput tissue microarray immunohistochemistry (TMA-IHC) with a TMA that includes 9 hemangiopericytomas (HPCs) and 41 meningiomas spanning all grades, as well as two subsets of atypical meningiomas, stratified according to clinical behavior. Antibodies utilized were progesterone receptor (PR), epithelial membrane antigen (EMA), cathepsin D, E-cadherin, platelet derived growth factor (PDGF) receptor beta, PDGF BB ligand, survivin, epithelial growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). In most cases, frequencies of tumor positivity were similar to those previously reported using whole section IHC. EMA, E-cadherin, and PDGFR-beta staining patterns distinguished the anaplastic meningiomas from the HPCs (P < 0.001, P = 0.02, P = 0.015, respectively). As in prior studies, PR and cathepsin D expression were inversely proportional to tumor grade. However, PR and EGFR were also differentially expressed between symptomatic, surgically resected benign meningiomas and incidental meningiomas found at autopsy. We conclude that (1) TMA-IHC is an accurate and efficient way to rapidly assess biomarkers in meningeal tumors, (2) EMA, E-cadherin, and PDGFR-beta are useful in distinguishing anaplastic meningiomas from HPCs, and (3) the expression patterns for incidental meningiomas differ slightly from their surgically resected symptomatic counterparts.
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PMID:High throughput screening of meningioma biomarkers using a tissue microarray. 1598 Sep 72

The role of two adipocytokines, adiponectin and leptin, in Taiwanese breast cancer patients remains to be determined. In this study, we analyzed the correlations between the serum levels of adiponectin and leptin and the various clinicopathological parameters in 100 newly diagnosed, histologically confirmed breast cancer patients and 100 controls. We found serum levels were decreased significantly for adiponectin in the breast cancer patients, in comparison to controls (Student t-test, P=0.003), while serum levels were increased significantly for leptin in the breast cancer patients in comparison to controls (Student t-test, P=0.025). Leptin/adiponectin (L/A ratio) were increased significantly in the breast cancer patients, in comparison to controls (Student t-test, P=0.009). Among the clinicopathological parameters, estrogen receptor, progesterone receptor, HER2/neu, lymph node metastasis, tumor stage, and tumor grade all showed no effect on the serum levels of adiponectin and leptin. BMI was negatively and positively correlated to serum adiponectin and leptin levels, respectively (Spearman's correlation, r=-0.333 and 0.323, respectively; P<0.001 for both). Intriguingly, serum L/A ratio disclosed a positive correlation to tumor size (r=0.21, P=0.036). In summary, our results suggest that low serum adiponectin levels and high serum leptin levels are associated with an increased risk for breast cancer. Also, independent of the effect of BMI, the increased serum ratio of L/A may indicate the presence of aggressive breast cancers.
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PMID:Serum adiponectin and leptin levels in Taiwanese breast cancer patients. 1601 38

The intention of this retrospective analysis was to describe the characteristics of patients with brain metastasis (BM) receiving trastuzumab for HER2 overexpressing metastatic breast cancer (MBC). A specific focus was the relation of BM occurrence to remission status of visceral disease during trastuzumab treatment. Patients with MBC presenting between March 2000 and May 2004 were included in this retrospective analysis. HER2 overexpression was determined by immunohistochemistry (IHC; DAKO Hercep Test). Trastuzumab was applied at a loading dose of 4 mg/kg and a maintenance dose of 2 mg/kg. Among 136 HER2 overexpressing patients (DAKO score 3+), 42 patients with BM were identified during follow-up (30.9%). Negative hormone receptor expression (estrogen receptor (ER) and progesterone receptor (PgR)) correlated with incidence of BM (42.8% vs. 23.4%; P=0.01). There was no correlation of the development of BM with regard to tumor grading and patient age. In patients who developed BM, the median interval between visceral and brain metastasis was 14 months (range 0-69 months). At the time BM was diagnosed, 14 out of 42 patients responded to trastuzumab-based treatment schedules (OR: 33.3%, 95% CI 18.5-48.2%). Median survival from diagnosis of BM was 13 months (range 0-60 months). The median overall survival calculated from first diagnosis of metastasis was not significantly shorter in patients with BM than in patients without BM (37 vs. 47 months; P=0.07 log rank). Trastuzumab is highly effective for the treatment of liver and lung metastasis in HER2 overexpressing patients, while it is apparently ineffective for treating or preventing BM. Since one third of HER2 overexpressing patients with MBC developed BM despite effective trastuzumab treatment, new treatment strategies and closer surveillance may be warranted for these patients.
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PMID:Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer. 1602 83

Fulvestrant ('Faslodex') is a new oestrogen receptor (ER) antagonist with no agonist effects. This report describes the experience of a single centre including 126 postmenopausal women with advanced breast cancer (ABC) in a fulvestrant Compassionate Use Programme. All patients had previously received endocrine treatment for early or ABC. Patients received fulvestrant as first- (n=7), second- (n=51), third- (n=50) or fourth-line endocrine therapy (n=18) for ABC (median duration of treatment: 4 months [range 3-27(+) months], follow-up: 13 months [range 1-38(+) months]). Twelve patients had partial responses (PR) and 43 patients experienced stable disease (SD) > or = 6 months (objective response rate: 9.5%; clinical benefit [CB] rate: 43.6%). Ten of 12 patients with a PR had HER2-negative tumours, and 9/12 had ER-positive and progesterone receptor (PgR)-positive disease (two patients had unknown HER2 status and one had unknown ER and PgR status). Nine of the 18 patients with HER2-positive tumours experienced CB with fulvestrant. Although CB rates were similar when fulvestrant was given as first- to fourth-line endocrine treatment, the proportion of those experiencing CB who had a PR appeared to decrease when fulvestrant was used later in the sequence. Fulvestrant was well tolerated; six patients experienced adverse events (all grade I/II). These data demonstrate that fulvestrant is an effective and well-tolerated therapy for patients with ABC progressing on prior therapies.
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PMID:Fulvestrant ('Faslodex') in pre-treated patients with advanced breast cancer: a single-centre experience. 1623 5

Recent biological studies have classified breast carcinomas into HER2-overexpressing, estrogen receptor-positive/luminal, basal- and normal-like groups. According to this new biological classification, the objectives of our study were to assess the clinical, morphologic and immunophenotypic characteristics of adenoid cystic carcinoma of the breast in order to classify this subtype of breast carcinoma. A total of 18 cases of adenoid cystic carcinoma were identified from the Institut Curie files. Clinical information was available for 16 patients with a median follow-up of 6.5 years. Morphologically, all tumors were graded according to the system defined by Kleer and Oberman (histologic and nuclear grade). Immunophenotype was assessed with anti-ER, PR, HER-2, KIT, basal (CK5/6) and luminal cytokeratins (CK8/18) and p63 antibodies. One out of 18 tumors was nuclear grade 1 (16%), nine were nuclear grade 2 (50%) and eight were nuclear grade 3 (44%). All cases were estrogen receptor, progesterone receptor and HER-2 negative. Epithelial cells were strongly positive around glandular lumina with one or both cytokeratins, identifying the coexistence of CK5/6+ cells, CK5/6 and CK8/18+ cells, CK8/18+ cells and p63+ cells. All cases (100%) were also KIT positive. In all, 15 patients were treated by surgery. Nine of them received adjuvant radiotherapy. Follow-up was available for 16 patients. In all, 14 patients were alive. Two of them, initially treated by surgery only, presented a local recurrence. Two patients died (one of them treated by radiation therapy only died from her disease). Our study shows that adenoid cystic carcinoma of the breast is a special, estrogen receptor, progesterone receptor, HER-2 negative and highly KIT-positive, basal-like breast carcinoma, associated with an excellent prognosis. This highly specific immunophenotype could be useful to differentiate adenoid cystic carcinoma of the breast from other subtypes of breast carcinoma such as cribriform carcinoma.
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PMID:KIT is highly expressed in adenoid cystic carcinoma of the breast, a basal-like carcinoma associated with a favorable outcome. 1625 15

ICI 182,780 (Faslodex), considered a pure anti-estrogen, is approved for treatment of post-menopausal breast cancer patients who fail to respond to tamoxifen therapy. We recently reported that, like mifepristone, ICI 182,780 exhibits anti-progestin activity, blocking the progestin-dependent increase in endogenous vascular endothelial growth factor (VEGF) mRNA and protein release. Some anti-progestins have partial agonist-like activity in breast cancer cells expressing high levels of progesterone receptor B (PRB). Our results show that ICI 182,780 can also induce reporter activity from a plasmid containing a simple progestin responsive element (PRE) in these cells. Using small interfering RNA, we determined that induction is dependent on the presence of PR, estrogen receptor and SRC-1. Regulation of more complex progestin-responsive promoters was context-dependent; induction was observed from the MMTV promoter but not from the VEGF promoter. In contrast, ICI 182,780 increased the release of angiogenically active VEGF from cells expressing elevated levels of PRB. This effect was dependent on the phosphatidylinositol-3 kinase and ERK/MAPK signaling pathways. We hypothesize that these agonist-like properties of ICI 182,780 (one genomic and one non-genomic) may contribute to the acquisition of drug resistance, suggesting that both anti-hormonal and anti-angiogenic treatment may be appropriate in these patients.
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PMID:Complex agonist-like properties of ICI 182,780 (Faslodex) in human breast cancer cells that predominantly express progesterone receptor-B: implications for treatment resistance. 1627 21

Endocrine therapy is the treatment of choice for patients with breast cancer expressing estrogen receptor (ER) and/or progesterone receptor. The efficacy of endocrine therapy is well established in the prevention, adjuvant and metastatic settings. However, either de novo or acquired resistance is frequently observed. Much effort has been made to elucidate the mechanisms of action underlying resistance to endocrine therapy in breast cancer, and several possible explanations have been suggested. Our previous studies have indicated that combined treatment with an antiestrogen, fulvestrant, and an inhibitor of the HER2 signaling pathway, trastuzumab, or an inhibitor of the HER1 signaling pathway, gefitinib, leads to an additive antitumor effect in breast cancer cells expressing ER and HER2 or HER1, respectively. It has also been suggested that the HER1 or HER2 signaling pathway is upregulated during the development of antiestrogen-resistant growth in breast cancer cells. These findings suggest that signal transduction inhibitors are effective for the treatment of antiestrogen-resistant breast cancer. A hypoxic microenvironment has been shown to promote malignant progression in cancer cells. Our previous study and others have suggested that hypoxia posttranscriptionally reduces ER expression and decreases sensitivity to hormonal agents in breast cancer cells. Our preliminary study has also shown that a hypoxic cytotoxin, tirapazamine, increases ER expression in breast cancer xenografts. Differential antitumor activity of tirapazamine on tumor cells under normoxic or hypoxic conditions may cause this phenomenon. These findings suggest that hypoxic cytotoxins may retard the development of endocrine resistance induced by hypoxia. Molecular mechanisms responsible for endocrine resistance in breast cancer are reviewed and possible therapeutic strategies against this resistance are discussed.
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PMID:Resistance to endocrine therapy in breast cancer. 1627 53


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