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)

Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all types of breast cancer and for a higher percentage of breast cancer arising in African and African-American women who are premenopausal. Because of the absence of specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, such treatment leaves them associated with a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). Analyses of microarray gene-expression profiling data show that they form a homogeneous group (or so-called cluster) in transcriptional terms and, increasingly, research studies are identifying basal cancers on the basis of exhibiting this distinctive transcriptional profile. Histologically and transcriptionally, triple-negative breast cancers have many similarities to BRCA1-associated breast cancers, which suggests that dysfunction in BRCA1 or related pathways occurs in this subset of sporadic cancers. In this review, we discuss the molecular features of triple-negative breast cancers and consider how the use of existing cytotoxic agents can be optimised for this patient group. We discuss the implications of a possible underlying BRCA1-pathway dysfunction in this subgroup in terms of treatment and we also investigate the predominant proliferative signals and the on-going research addressing the suitability of these signals as therapeutic targets.
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PMID:Triple-negative breast cancer: therapeutic options. 1732 94

Analysis of gene expression data suggests that breast cancers are divisible into molecular subtypes which have distinct clinical features. This study evaluates whether pathologic features and etiologic associations differ among molecular subtypes. We evaluated 804 women with invasive breast cancers and 2,502 controls participating in a Polish Breast Cancer Study. Immunohistochemical stains for estrogen receptor alpha, progesterone receptor, human epidermal growth factor receptors (HER2 and HER1), and cytokeratin 5 were used to classify cases into five molecular subtypes: luminal A, luminal B, HER2-expresing, basal-like, and unclassified. Relative risks were estimated using adjusted odds ratios and 95% confidence intervals. We observed that compared with the predominant luminal A tumors (69%), other subtypes were associated with unfavorable clinical features at diagnosis, especially HER2-expressing (8%) and basal-like (12%) tumors. Increasing body mass index significantly reduced the risk of luminal A tumors among premenopausal women (odds ratios, 0.71; 95% confidence intervals, 0.57-0.88 per five-unit increase), whereas it did not reduce risk for basal-like tumors (1.18; 0.86-1.64; P(heterogeneity) = 0.003). On the other hand, reduced risk associated with increasing age at menarche was stronger for basal-like (0.78; 0.68-0.89 per 2-year increase) than luminal A tumors (0.90; 0.95-1.08; P(heterogeneity) = 0.0009). Although family history increased risk for all subtypes (except for unclassified tumors), the magnitude of the relative risk was highest for basal-like tumors. Results from this study have shown that breast cancer risk factors may vary by molecular subtypes identified in expression studies, suggesting etiologic, in addition to clinical, heterogeneity of breast cancer.
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PMID:Differences in risk factors for breast cancer molecular subtypes in a population-based study. 1737 38

A recent report indicated that a high prevalence of basal-like breast tumors (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative, human epidermal growth factor receptor [HER] 2-negative, and cytokeratin 5/6-positive and/or HER1-positive) could contribute to a poor prognosis in African American women with breast cancer. It has been reported that Japanese women with breast cancer have a significantly better survival rate than other races in the USA. These findings suggest that breast cancers in Japanese women have favorable biological characteristics. To clarify this hypothesis, we conducted a cohort study to investigate the prevalence of intrinsic subtypes and prognosis for each subtype in 793 Japanese patients. This study revealed a very low prevalence (only 8%) of basal-like breast tumors with aggressive biological characteristics in Japanese patients. Survival analysis showed a significantly poorer prognosis in patients with basal-like tumors than in those with luminal A tumors (ER- and/or PR-positive, and HER2-negative) with favorable biological characteristics. These findings support the hypothesis that breast cancers in Japanese women have more favorable biological characteristics and a better prognosis than those in other races. In conclusion, the prevalence of basal-like breast tumors could influence the prognosis of breast cancer patients of different races. The prevalence of intrinsic subtypes should be taken into account when analyzing survival data in a multi-racial/international clinical study.
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PMID:The prevalence of intrinsic subtypes and prognosis in breast cancer patients of different races. 1771 47

Basal-like breast carcinoma is an aggressive form of breast cancer, characterized by the absence of oestrogen receptor and HER2 expression, the presence of cytokeratin 5 and epidermal growth factor receptor expression, and by the up-regulation of stem cell regulatory genes. We show here that tumour tissues expressing high levels of SLUG mRNA show a basal-like breast carcinoma phenotype and that such tumours also express high levels of stem cell-regulatory genes, ie CD133, Bmi1. Further, we show that stem/progenitor cells, isolated from ductal breast carcinoma and from normal mammary gland as mammospheres, express SLUG, CD133, and Bmi1 mRNA and show a phenotype similar to that of basal-like breast carcinoma. We also report that SLUG expression in tumour tissues correlates with that of the hypoxia survival gene carbonic anhydrase IX. In this regard, we report that the exposure of SLUG-negative/luminal-like MCF-7 cells to a hypoxic environment promotes the onset of the basal-like breast carcinoma phenotype, together with up-regulation of the SLUG gene, which in turn blunts oestrogen receptor-alpha and boosts carbonic anhydrase IX gene expression. Finally, we show that SLUG expression promotes the invasiveness of MCF-7 cells exposed to hypoxia and sustains the in vivo aggressiveness of hypoxia-selected, MCF-7-derived cells in xenografts. These data indicate that SLUG gene expression is part of a hypoxia-induced genetic programme which sets up a basal/stem cell-like, aggressive phenotype in breast cancer cells.
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PMID:The basal-like breast carcinoma phenotype is regulated by SLUG gene expression. 1797 39

Metaplastic breast carcinoma, a rare tumor composed of adenocarcinomatous and nonglandular growth patterns, is characterized by a propensity for distant metastases and resistance to standard anticancer therapies. We sought confirmation that this tumor is a basal-like breast cancer, expressing epidermal growth factor receptor (EGFR) and stem cell factor receptor (KIT). EGFR activating mutations and high copy number (associated with response to tyrosine kinase inhibitor gefitinib) and KIT activating mutations (associated with imatinib sensitivity) were then investigated. Seventy-seven metaplastic cases were identified (1976-2006); 38 with tumor blocks available underwent pathologic confirmation before EGFR and KIT immunohistochemical analyses. A tissue microarray of malignant glandular and metaplastic elements was constructed and analyzed immunohistochemically for cytokeratin 5/6, estrogen receptor, progesterone receptor, and p63, and by fluorescence in situ hybridization for EGFR and HER-2/neu. DNA isolated from individual elements was assessed for EGFR and KIT activating mutations. All assessable cases were negative for estrogen receptor, progesterone receptor, and (except one) HER2. The majority were positive for cytokeratin 5/6 (58%), p63 (59%), and EGFR overexpression (66%); 24% were KIT positive. No EGFR or KIT activating mutations were present; 26% of the primary metaplastic breast carcinomas were fluorescence in situ hybridization-positive, displaying high EGFR copy number secondary to aneusomy (22%) and amplification (4%). We report here that metaplastic breast carcinoma is a basal-like breast cancer lacking EGFR and KIT activating mutations but exhibiting high EGFR copy number (primarily via aneusomy), suggesting that EGFR tyrosine kinase inhibitors should be evaluated in this molecular subset of breast carcinomas.
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PMID:Molecular analysis of metaplastic breast carcinoma: high EGFR copy number via aneusomy. 1841 8

To update the data on the expression of 'mesothelioma markers' by serous carcinomas of various sites we have studied cases from ovary (n=56), endometrium (n=37), fallopian tube (n=6), primary peritoneum (n=5) and cervix (n=3) using a panel of antibodies (WT1, P53, estrogen receptors, HER2/neu, D2-40, cytokeratin 5/6 and E-cadherin). Ovarian carcinomas demonstrated D2-40 and cytokeratin 5/6 immunoreactivity in 23.2 and 55.4% of cases, respectively. Endometrial carcinomas demonstrated D2-40 and cytokeratin 5/6 immunoreactivity in 43.2 and 37.8% of cases, respectively. D2-40 staining pattern was predominantly focal; however, strong reactivity was identified in 16.2% of endometrial and 10.7% of ovarian carcinomas. HER2/neu oncoprotein overexpression was demonstrated in 7 of 37 (18.9%) uterine serous carcinomas. In contrast, all the serous carcinomas of the other sites were HER2/neu negative. The proportion of positive cases was significantly different in ovarian vs endometrial carcinomas regarding WT1 (P=0.0458), estrogen receptors (P<0.001) reactivity and HER2/neu overexpression (P=0.0025). D2-40 and cytokeratin 5/6 are expressed in a considerable proportion of serous carcinomas and should be used cautiously in a 'mesothelioma panel' in situations where serous carcinoma is in the differential diagnosis. HER2/neu was exclusively overexpressed in serous carcinomas of endometrial origin.
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PMID:Immunophenotyping of serous carcinoma of the female genital tract. 1856 94

Gene expression studies have identified a basal phenotype of breast cancer; these are hormone receptor and HER2-negative cancers with poor prognosis. High levels of cyclin E and Skp2, and low levels of p27 have previously been individually associated with both basal-like breast cancer and a poor outcome after diagnosis. The goal of this study was to first confirm the prognostic value of these biomolecular markers using a breast cancer tissue microarray. Second, we also test the hypothesis that the combined phenotype of high cyclin E, low p27, and high Skp2 would be a strong predictor of outcome and would be closely associated with the basal phenotype of breast cancer. Our cohort consisted of 438 cases of breast cancer and the median follow-up was 15.4 years. The tissue microarray was constructed from archival tumor blocks and we used commercially available antibodies for biomarker immunostaining. Cyclin E was positive in 46% of cases, p27 was negative in 62%, and Skp2 was positive in 35%. We found cyclin E and Skp2 to be prognostic for breast cancer-specific survival in univariate analyses, but p27 was not prognostic. The strongest predictor of outcome was the combination of cyclin E positive and Skp2 positive (difference in survival of 19% at 10 years, P = .0009). This combination was present in 78 (27%) of 288 cases for which data on both biomarkers were available. This combination was also highly associated with young age at diagnosis, grade 3 tumors, ER-negative status, HER2-negative status, and the basal biomarkers epidermal growth factor receptor and cytokeratin 5/6. However, in a multivariate model including standard clinicopathologic variables, this combination was not found to have independent prognostic significance. In conclusion, the combination of high cyclin E and Skp2 expression predicts for poor prognosis in breast cancer in univariate analysis only, it is associated with high risk features, and it is associated with the basal phenotype.
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PMID:The combination of high cyclin E and Skp2 expression in breast cancer is associated with a poor prognosis and the basal phenotype. 1862 Jul 30

Breast cancer in the young is considered a special clinical presentation of the disease. Sixty-nine breast cancer cases diagnosed at or before the age of 35 were analyzed for common morphological and immunophenotypical features of basal-like carcinomas. Sixteen carcinomas displayed the immunophenotypical characteristics (estrogen receptor and HER2 negativity and positivity for at least one of the following basal markers: cytokeratin 5 or 14, epidermal growth factor receptor, p63) of basal-like carcinomas, and most of them demonstrated characteristic histological features (pushing borders, lymphocytic peritumoral infiltrate, central hypocellular zone or necrosis, high mitotic rate) too. These tumors were more likely to be high-molecular-weight cytokeratin: 34betaE12 and p53 positive by immunohistochemistry. The presence of a basal-like phenotype can be important as concerns systemic treatment issues and could theoretically be associated with a higher rate of BRCA1 mutations in the young, because of the overlap of BRCA1 mutation associated breast carcinomas and the basal-like phenotype.
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PMID:Basal phenotype in breast carcinoma occurring in women aged 35 or younger. 1875 48

Claudins (CLDN) are tight junction proteins which contribute to the paracellular transport and ionic permeability of various epithelia. In recent years they came into focus for their suggested role in carcinogenesis and possible role in cancer therapy. According to our previous studies, in breast tissue CLDN4 is also related to the level of cellular differentiation. Thirty-eight estrogen (ER) and progesterone receptor (PgR) negative, HER2/neu negative, but cytokeratin 5/6 positive basal-like-mainly grade 3-breast carcinomas were compared with twenty-one grade 1, twenty-five grade 2 and twenty grade 3 non-basal-like invasive breast carcinomas, in respect to their CLDN4 expression. The immunohistochemical reactions were evaluated both semiquantitatively and by morphometrical analysis. Statistically significant difference (p = 0.001) was observable regarding CLDN4 expression in the basal-like group as compared to grade 1 and 2 cancers. Further, CLDN4 expression was significantly higher (p = 0.017) in the basal-like compared with the non-basal-like grade 3 carcinomas. Our results suggest that basal-like carcinomas are a subset of breast cancer with high level of CLDN4 protein expression. The finding is in accordance with our former observation that CLDN4 is indeed related to cellular differentiation. This observation may be seen as a further proof that basal-like carcinomas represent a separable group amongst grade 3 breast carcinomas.
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PMID:Expression of tight junction protein claudin-4 in basal-like breast carcinomas. 1875 49

Traditional prognostic markers for breast cancer include estrogen receptor (ER), progesterone receptor (ER) and HER2/neu. Negative staining for these three markers defines the 'triple-negative' phenotype. By adding markers for cytokeratin 5/6 and EGFR, triple-negative breast cancers can be divided into 'basal-like' and 'normal-like' subgroups. We conducted immuno-staining on a panel of 958 patients with breast cancer, using all five markers and we followed the patients for distal recurrence and death. We compared rates of distal recurrence in the basal-like and normal-like subgroups with that of women with ER-positive breast cancer. Only 16 of 958 women had normal-like breast cancers. These cancers resembled basal-like cancers in that they had a high proliferative index, but the women with normal-like breast cancers resembled ER-positive women in terms of distant recurrence. The addition of CK5/6 and EGFR to the standard panel (ER/PR/HER2/neu) defines a small subgroup of women with normal-like breast cancer. The prognosis of these women may be superior to that of basal-like breast cancers but firm conclusions cannot be made.
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PMID:Patterns of recurrence in the basal and non-basal subtypes of triple-negative breast cancers. 1918 11


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