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)

Oestrogen receptor (ER)-negative breast cancer, including oestrogen receptor-, progesterone receptor- and human epidermal growth factor receptor 2-negative (ER/PR/HER2-negative) breast cancer, is more aggressive than ER-positive disease. A major limitation in the treatment of ER-negative disease subtypes is the inherent insensitivity to hormonal agents (tamoxifen, aromatase inhibitors) that are widely used in the treatment of breast cancer. Thus, therapeutic options for poor prognosis patients with ER-negative breast cancer are limited to a handful of chemotherapeutic agents, and new agents are needed to improve the treatment of this disease. Ixabepilone, a novel epothilone B analogue with low susceptibility to cellular mechanisms that confer resistance to taxanes and other chemotherapeutic agents, has demonstrated potent preclinical antitumour activity in multiple models, including those with primary or acquired drug resistance. This review summarises the results of a prospective subset analysis from a phase III clinical trial evaluating ixabepilone for the treatment of metastatic breast cancer (MBC), in which efficacy and safety were evaluated in patients with ER-negative and ER/PR/HER2-negative disease.
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PMID:Activity of ixabepilone in oestrogen receptor-negative and oestrogen receptor-progesterone receptor-human epidermal growth factor receptor 2-negative metastatic breast cancer. 1968 29

Breast cancer is a heterogeneous disease caused by the accumulation of genetic changes in neoplastic cells. We hypothesised that molecular subtypes of breast cancer may be driven by specific constellations of genes whose expression is regulated by gene copy number aberrations. To address this question, we analysed a series of 48 microdissected grade III ductal carcinomas using high resolution microarray comparative genomic hybridisation and mRNA expression arrays. There were 5,931 genes whose expression significantly correlates with copy number identified; out of these, 1,897 genes were significantly differentially expressed between basal-like, HER2 and luminal tumours. Ingenuity Pathway Analysis (IPA) revealed that 'G1/S cell cycle regulation' and 'BRCA1 in DNA damage control' pathways were significantly enriched for genes whose expression correlates with copy number and are differentially expressed between the molecular subtypes of breast cancer. IPA of genes whose expression significantly correlates with copy number in each molecular subtype individually revealed that canonical pathways involved in oestrogen receptor (ER) signalling and DNA repair are enriched for these genes. We also identified 32, 157 and 265 genes significantly overexpressed when amplified in basal-like, HER2 and luminal cancers, respectively. These lists include known and novel potential therapeutic targets (e.g. HER2 and PPM1D in HER2 cancers). Our results provide strong circumstantial evidence that different patterns of genetic aberrations in distinct molecular subtypes of breast cancer contribute to their specific transcriptomic profiles and that biological phenomena characteristic of each subtype (e.g. proliferation, HER2 and ER signalling) may be driven by specific patterns of copy number aberrations.
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PMID:An integrative genomic and transcriptomic analysis reveals molecular pathways and networks regulated by copy number aberrations in basal-like, HER2 and luminal cancers. 1968 61

The aim of the current study was to assess the expression levels of c-Src and phosphorylated Src kinase in human breast cancers and to establish if these are linked to oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status or patient survival. Tissue microarray technology was used to analyze 314 breast cancer specimens. Immunohistochemistry was performed using antibodies to c-Src, Y419Src, and Y215Src, and expression was assessed using the weighted histoscore method. High cytoplasmic c-Src kinase and high membrane phosphorylated activated Y419Src kinase was associated with decreased disease-specific survival. In contrast, phosphorylated activated nuclear and cytoplasmic Y215Src kinase expression levels were significantly associated with improved disease-specific survival. When the cohort was subdivided according to ER/PR/HER2 status, the ER-negative subgroup (105 patients) was associated with improved disease-specific survival and was found to be independent by multivariate analysis with a hazard ratio of 0.4 (interquartile range 0.2-0.8). High cytoplasmic c-Src expression was associated with decreased survival; high expression of activated c-Src (Y215) was associated with improved survival. This was potentiated in the ER/HER2-negative subgroup. Hence, administration of Src kinase inhibitors aiming to decrease phosphorylation should be approached with caution, especially in ER-negative patients. It is therefore essential to appropriately identify with the correct biomarkers which patients are most likely to respond to Src inhibitors.
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PMID:Is expression or activation of Src kinase associated with cancer-specific survival in ER-, PR- and HER2-negative breast cancer patients? 1976 12

The dietary isothiocyanates (ITCs) exhibit strong chemopreventive activities for a variety of neoplasms including breast cancer. However, the molecular mechanisms underlying ITC function in breast cancer cells have not been well established. Here, we found that phenethyl isothiocyanate (PEITC) acted more potently than the 'pure' anti-oestrogen ICI 182,780 to inhibit the growth of oestrogen receptor (ER)(+) breast cancer MCF7 and H3396 cells and ER(-) MDA-MB-231 and SK-BR-3 cells. PEITC reduced the steady state levels of ER-alpha and its novel variant, ER-alpha36 in a dose-and time-dependent manner and inhibited oestrogen-induced activation of the mitogen activated protein kinase/ERK 1/2 signaling pathway. However, ICI 182,780 that is potent in destabilization of ER-alpha protein, failed to down-regulate ER-alpha36. Our results thus demonstrated that PEITC functions as a more potent ER-alpha'disruptor' than the well-known ICI 182,780 to abrogate ER-mediated mitogenic oestrogen signaling in breast cancer cells, which provides a molecular explanation for the strong growth inhibitory activity of ITCs in breast cancer cells, and a rational for further exploration of ITCs as chemopreventive agents for human mammary carcinogenesis.
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PMID:Breast cancer cell growth inhibition by phenethyl isothiocyanate is associated with down-regulation of oestrogen receptor-alpha36. 1984 Jan 89

CCND1 encodes for the cyclin D1 protein involved in G1/S cell cycle transition. In breast cancer the mechanism of CCND1 amplification, relationship between cyclin D1 protein expression and the key clinical markers estrogen receptor (ER) and HER2 requires elucidation. Tissue microarrays of primary invasive breast cancer from 93 women were evaluated for CCND1 amplification by fluorescent in-situ hybridization and cyclin D1 protein overexpression by immunohistochemistry. CCND1 amplification was identified in 27/93 (30%) cancers and 59/93 (63%) cancers had overexpression of cyclin D1. CCND1 amplification was significantly associated with cyclin D1 protein overexpression (p < 0.001; Fisher's exact test) and both CCND1 amplification and cyclin D1 protein expression with oestrogen receptor (ER) expression (p = 0.003 and p < 0.001; Fishers exact test). Neither CCND1 amplification nor cyclinD1 expression was associated with tumor size, pathological node status or HER2 amplification, but high CCND1 amplification (Copy Number Gain (CNG) > or = 8) was associated with high tumor grade (p = 0.005; chi square 7.915, 2 df) and worse prognosis by Nottingham Prognostic Index (p = 0.001; 2 sample t-test). High CCND1 amplification (CNG > or = 8) may identify a subset of patients with poor prognosis ER-positive breast cancers who should be considered for additional therapy.
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PMID:High CCND1 amplification identifies a group of poor prognosis women with estrogen receptor positive breast cancer. 1990 58

We report a prospective study of women over 70 years of age with early breast cancer who had primary endocrine treatment. Core biopsies of the cancer were taken at diagnosis and assessed using immunohistochemistry for oestrogen receptor (ER), progesterone receptor (PgR), epidermal growth factor receptor (EGFR), pS2, cyclin D1, p21, p53, HER2 and MIB1 (Ki67). Outcome analysis was performed at a median follow-up of 70 months. Correlation was sought between tumour marker measurements and disease control. When all patients were considered, a significant relationship was found between the absence of ER and PgR, the presence of p53 and EGFR, and high MIB1 and treatment failure. However, for the ER positive cancers, no other marker predicted treatment failure or relapse. There remains an important clinical need to identify those ER positive breast cancers that will not respond to endocrine treatment, and those in which the response will be short-lived.
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PMID:Tumour markers predictive of successful treatment of breast cancer with primary endocrine therapy in patients over 70 years old: a prospective study. 1996 69

Epidemiological, clinical, and molecular studies suggest a role for oestrogen in thyroid cancer. How oestrogen mediates its effects and the consequence of it on clinical outcome has not been fully elucidated. The participation of coregulatory proteins in modulating oestrogen receptor (ER) function and input of crosstalk with the tyrosine kinase receptor HER2 was investigated. Oestrogen induced cell proliferation in the follicular thyroid cancer (FTC)-133 cells, but not in the anaplastic 8305C cell line. Knockdown of the coactivator steroid receptor coactivator (SRC)-1 inhibited FTC-133 basal, but not oestrogen induced, cell proliferation. Oestrogen also increased protein expression of SRC-1 and the ER target gene cyclin D1 in the FTC-133 cell line. ERalpha, ERbeta, the coregulatory proteins SRC-1 and nuclear corepressor (NCoR), and the tyrosine kinase receptor HER2 were localised by immunohistochemistry and immnofluorescence in paraffin-embedded tissue from thyroid tumour patients (n=111). ERalpha was colocalised with both SRC-1 and NCoR to the nuclei of the tumour epithelial cells. Expression of ERalpha and NCoR was found predominantly in non-anaplastic tumours and was significantly associated with well-differentiated tumours and reduced incidence of disease recurrence. In non-anaplastic tumours, HER2 was significantly associated with SRC-1, and these proteins were associated with poorly differentiated tumours, capsular invasion and disease recurrence. Totally, 87% of anaplastic tumours were positive for SRC-1. Kaplan-Meier estimates of disease-free survival indicated that in thyroid cancer, SRC-1 strongly correlates with reduced disease-free survival (P<0.001), whereas NCoR predicted increased survival (P<0.001). These data suggest opposing roles for the coregulators SRC-1 and NCoR in thyroid tumour progression.
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PMID:The role of oestrogen receptor {alpha} in human thyroid cancer: contributions from coregulatory proteins and the tyrosine kinase receptor HER2. 2003 8

Several studies have demonstrated that familial breast cancers associated with BRCA1 or BRCA2 germline mutations differ in their morphological and immunohistochemical characteristics. Cancers associated with BRCA1 are poorly differentiated infiltrating ductal carcinomas (IDCs) with higher mitotic counts and pleomorphism and less tubule formation than sporadic tumours. In addition, more cases with the morphological features of typical or atypical medullary carcinoma are seen in these patients. Breast carcinomas from BRCA2 mutation carriers tend to be of higher grade than sporadic age-matched controls. Regarding immunophenotypic features. BRCA1 tumours have been found to be more frequently oestrogen receptor- (ER) and progesterone receptor-(PR) negative, and p53-positive than age-matched controls, whereas these differences are not usually found in BRCA2-associated tumours. A higher frequency and unusual location of p53 mutations have been described in BRCA1/2 carcinomas. Furthermore, BRCA1- and BRCA2-associated breast carcinomas show a low frequency of HER-2 expression. Recent studies have shown that most BRCA1 carcinomas belong to the basal cell phenotype, a subtype of high grade, highly proliferating ER/HER2-negative breast carcinoma characterized by the expression of basal or myoepithelial markers, such as basal keratins, P-cadherin, EGFR, etc. This phenotype occurs with a higher incidence in BRCA1 tumours than in sporadic carcinomas and is rarely found in BRCA2 carcinomas. Hereditary carcinomas not attributable to BRCA1/2 mutations have phenotypic similarities with BRCA2 tumours, but tend to be of lesser grade and lower proliferation index. The pathological features of hereditary breast cancer can drive specific treatment and influence the process of mutation screening.
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PMID:The pathology of hereditary breast cancer. 2023 67

There is growing evidence that uncontrolled activation of the PI3K/Akt/mTOR pathway contributes to the development and progression of breast cancer. Inhibition of this pathway has antitumour effects in preclinical studies and efficacy in combination with other agents in breast cancer patients. The aim of this study is to characterise the effects of pre-operative everolimus treatment in primary breast cancer patients and to identify potential molecular predictors of response. Twenty-seven patients with oestrogen receptor (ER)-positive breast cancer completed 11-14 days of neoadjuvant treatment with 5-mg everolimus. Core biopsies were taken before and after treatment and analysed using Illumina HumanRef-8 v2 Expression BeadChips. Changes in proliferation (Ki67) and phospho-AKT were measured on diagnostic core biopsies/resection samples embedded in paraffin by immunohistochemistry to determine response to treatment. Patients that responded to everolimus treatment with significant reductions in proliferation (fall in % Ki67 positive cells) also had significant decreases in the expression of genes involved in cell cycle (P = 8.70E-09) and p53 signalling (P = 0.01) pathways. Highly proliferating tumours that have a poor prognosis exhibited dramatic reductions in the expression of cell cycle genes following everolimus treatment. The genes that most clearly separated responding from non-responding pre-treatment tumours were those involved with protein modification and dephosphorylation, including DYNLRB2, ERBB4, PTPN13, ULK2 and DUSP16. The majority of ER-positive breast tumours treated with everolimus showed a significant reduction in genes involved with proliferation, these may serve as markers of response and predict which patients will derive most benefit from mTOR inhibition.
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PMID:Gene expression profiling of response to mTOR inhibitor everolimus in pre-operatively treated post-menopausal women with oestrogen receptor-positive breast cancer. 2048 Feb 26

Increasingly more coherent data on the molecular characteristics of benign breast lesions and breast cancer precursors have led to the delineation of new multistep pathways of breast cancer progression through genotypic-phenotypic correlations. It has become apparent that oestrogen receptor (ER)-positive and -negative breast lesions are fundamentally distinct diseases. Within the ER-positive group, histological grade is strongly associated with the number and complexity of genetic abnormalities in breast cancer cells. Genomic analyses of high-grade ER-positive breast cancers have revealed that a substantial proportion of these tumours harbour the characteristic genetic aberrations found in low-grade ER-positive disease, suggesting that at least a subgroup of high-grade ER-positive breast cancers may originate from low-grade lesions. The ER-negative group is more complex and heterogeneous, comprising distinct molecular entities, including basal-like, HER2 and molecular apocrine lesions. Importantly, the type and pattern of genetic aberrations found in ER-negative cancers differ from those of ER-positive disease. Here, we review the available molecular data on breast cancer risk indicator and precursor lesions, the putative mechanisms of progression from in situ to invasive disease, and propose a revised model of breast cancer evolution based on the molecular characteristics of distinct subtypes of in situ and invasive breast cancers.
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PMID:Breast cancer precursors revisited: molecular features and progression pathways. 2050 Feb 30


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