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)

Expression profiling studies have suggested that HER2-amplified breast cancers constitute a heterogeneous group that may be subdivided according to their ER status: HER2-amplified ER-positive breast carcinomas that fall into the luminal B cluster; and HER2-amplified ER-negative cancers which form a distinct molecular subgroup, known as the erbB2 or HER2 subgroup. ER-negative breast cancer differs significantly from ER-positive disease in the pattern, type, and complexity of genetic aberrations. Here we have compared the genomic profiles of ER-positive and ER-negative HER2-amplified cancers using tiling path microarray-based comparative genomic hybridization (aCGH). Validation of the differentially amplified regions was performed in an independent series of 70 HER2-amplified breast cancers. Although HER2-amplified cancers had remarkably complex patterns of molecular genetic aberrations, ER-positive and ER-negative HER2-amplified breast carcinomas shared most molecular genetic features as defined by aCGH. Genome-wide Fisher's exact test analysis revealed that less than 1.5% of the genome was significantly differentially gained or lost in ER-positive versus ER-negative HER2-amplified cancers. However, two regions of amplification were significantly associated with ER-positive carcinomas, one of which mapped to 17q21.2 and encompassed GJC1, IGFBP4, TNS4, and TOP2A. Chromogenic in situ hybridization analysis of an independent validation series confirmed the association between ER status and TOP2A amplification. In conclusion, although hormone receptor status does not determine the overall genetic profile of HER2-amplified breast cancers, specific genetic aberrations may be characteristic of subgroups of HER2 breast cancers.
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PMID:The genomic profile of HER2-amplified breast cancers: the influence of ER status. 1881 Jul 58

Invasive ductal carcinomas (IDC) of the breast with the triple negative phenotype (steroid hormone receptor absent, negative HER2 status) are characterized by poor clinical outcome. Additional tumor markers might allow identification of patients at higher risk. We evaluated clinical and biological features of 284 consecutive patients with pT1-3, pN1-3 M0 triple-negative IDC. Median follow-up was 70 months (interquartile range 59-94 months). Statistically significant worse disease-free and overall survival were observed in multivariate analysis, for patients with EGFR immunoreactivity in >or=50% invasive tumor cells (HR 2.39, 95% CI, 1.32-4.34, P = 0.004 for DFS; HR 2.34, 95% CI, 1.20-4.59 P = 0.01 for OS). Age >or= 70 years and PVI were additional independent predictors of reduced overall survival. EGFR immunoreactivity significantly correlates with worse prognosis in patients with triple-negative IDC, supporting further studies on the correlation between the degree of EGFR expression and outcome of triple negative breast cancer.
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PMID:Invasive ductal carcinoma of the breast with the "triple-negative" phenotype: prognostic implications of EGFR immunoreactivity. 1883 7

Steroid hormone receptor expression and HER2 status have become an integral part of histopathologic characterization of breast cancer and corresponding biomarker assays have gained important prognostic and predictive impact. Because testing inaccuracy could provide a major hazard to modern breast cancer therapy, a laboratory proficiency testing program has been implemented in Germany using tissue microarrays (TMAs). In four consecutive annual trials with 142 laboratories participating on average per trial, estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (Her2) were determined immunohistochemically by participating laboratories followed by central review of all immunostains. Performance strongly depended on the ambiguity of expression of the target molecule in the test samples. In clearly positive (Allred score 7-8; Her2 3+) or negative tissue samples, the majority of participants (86%) achieved concordance rates exceeding 85%. By contrast, low expression of ER or PR (Allred score 3-4) as well as Her2 status 2+ led to considerable lower concordance rates ranging from 41% (Her2 2+) to 75% (PR). Poor reproducibility was predominantly due to inadequate laboratory performance whereas interobserver agreement (weighted kappa statistics) usually was high (>0.81). Laboratories that participated in more than one of the four subsequent trials (n = 110) showed a highly significant improvement of performance. In conclusion, a TMA-based proficiency testing of biomarkers in breast cancer has been implemented in Germany over a 5-year period and revealed reliable assessment of unambiguously positive and negative test samples. Low-expressing tumor samples with regard to steroid hormone receptor expression and Her2 status 2+ led to inaccurate evaluations by up to 59% of participants. Regularly participating laboratories showed a significant improvement of performance.
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PMID:Proficiency testing of immunohistochemical biomarker assays in breast cancer. 1895 94

Whereas target-specific drugs are available for treating ERBB2-overexpressing and hormone receptor-positive breast cancers, no tailored therapy exists for hormone receptor- and ERBB2-negative ("triple-negative") mammary carcinomas. Triple-negative tumors account for 15% of all breast cancers and frequently harbor defects in DNA double-strand break repair through homologous recombination (HR), such as BRCA1 dysfunction. The DNA-repair defects characteristic of BRCA1-deficient cells confer sensitivity to poly(ADP-ribose) polymerase 1 (PARP1) inhibition, which could be relevant to treatment of triple-negative tumors. To evaluate PARP1 inhibition in a realistic in vivo setting, we tested the PARP inhibitor AZD2281 in a genetically engineered mouse model (GEMM) for BRCA1-associated breast cancer. Treatment of tumor-bearing mice with AZD2281 inhibited tumor growth without signs of toxicity, resulting in strongly increased survival. Long-term treatment with AZD2281 in this model did result in the development of drug resistance, caused by up-regulation of Abcb1a/b genes encoding P-glycoprotein efflux pumps. This resistance to AZD2281 could be reversed by coadministration of the P-glycoprotein inhibitor tariquidar. Combination of AZD2281 with cisplatin or carboplatin increased the recurrence-free and overall survival, suggesting that AZD2281 potentiates the effect of these DNA-damaging agents. Our results demonstrate in vivo efficacy of AZD2281 against BRCA1-deficient breast cancer and illustrate how GEMMs of cancer can be used for preclinical evaluation of novel therapeutics and for testing ways to overcome or circumvent therapy resistance.
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PMID:High sensitivity of BRCA1-deficient mammary tumors to the PARP inhibitor AZD2281 alone and in combination with platinum drugs. 1897 40

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

Single markers are insufficient to accurately assess risk of relapse for adjuvant therapy guidance in operable breast cancer patients. In addition, the accuracy and interpretability of current multi-marker tests is generally limited by their simply additive algorithms and their overlap with clinicopathologic risks. Here, we report the development and validation of a nonlinear algorithm that combines protein (ER, PGR, ERBB2, BCL2 and TP53) and genomic (MYC/8q24) markers with standard clinicopathologic features (tumor size, tumor grade and nodal status) into a global risk assessment profile. The algorithm was trained using statistical pattern recognition in 200 stage I-III hormone receptor-positive patients treated with hormone therapy. Continuous risk scores (0-10+) were then generated for 232 independent patients. In hormone therapy-treated patients, the profile achieved a hazard ratio of 6.2 (95% confidence interval [CI], 1.8-20) in high- vs. low-risk groups for time to distant metastasis with the low-risk group having a 10-year metastasis rate of just 4% (95% CI, 0-8%). Similar results were achieved in untreated patients and for disease-specific survival. In multivariate analyses with standard prognostic factors and clinical practice guidelines, the profile was the only significant variable. Furthermore, the profile reclassified as low risk over half of node-negative patients at elevated risk according to the guidelines, which could have spared such patients from unnecessary cytotoxic chemotherapy. It also accurately identified a group of high-risk patients within a guideline low-risk group. In summary, the profile intelligently combines biologically relevant marker pathways and established clinicopathologic risks to help guide breast cancer patients to the most appropriate level of adjuvant therapy.
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PMID:Prognostic marker profile to assess risk in stage I-III hormone receptor-positive breast cancer patients. 1903 52

Breast cancer is a heterogeneous disease, and risk factors could be differentially associated with the development of distinct tumor subtypes that manifest different biological behavior and progression. In support of this view, there is growing evidence that known breast cancer risk factors vary by hormone receptor status and perhaps other pathologic characteristics of disease. Recent work from large consortial studies has led to the discovery of novel breast cancer susceptibility loci in genic (CASP8, FGFR2, TNRC9, MAP3K1, LSP1) and nongenic regions (8q24, 2q35, 5p12) of the genome, and to the finding of substantial heterogeneity by tumor characteristics. In particular, susceptibility loci in FGFR2, TNRC9, 8q24, 2q35, and 5p12 have stronger associations for estrogen receptor-positive (ER+) disease than estrogen receptor-negative (ER -) disease. These findings suggest that common genetic variants can influence the pathologic subtype of breast cancer, and provide further support for the hypothesis that ER+ and ER(-) disease result from different etiologic pathways. Current studies had limited power to detect susceptibility loci for less common tumor subtypes, such as ER(-) disease including triple-negative and basal-like tumors. Ongoing work targeting uncommon subtypes is likely to identify additional tumor-specific susceptibility loci in the near future. Characterization of etiologic heterogeneity of breast cancer may lead to improvements in the understanding of the biological mechanisms for breast cancer, and ultimately result in improvements in prevention, early detection, and treatment.
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PMID:Genetic susceptibility loci for breast cancer by estrogen receptor status. 1908 16

Carcinosarcoma of the breast, often referred to as metaplastic carcinoma of the breast, is a rare malignancy with two distinct cell lines described as a breast carcinoma of ductal type with a sarcoma-like component. Clinically, carcinosarcoma of the breast is an aggressive breast cancer. The prognosis for carcinosarcoma of the breast is less favorable compared to more common types of breast cancer such as infiltrating ductal or lobular carcinoma. Currently, the evaluation of breast carcinoma includes hormone receptor analysis of the tumor tissue, with those positive for estrogen or progesterone responding better to both hormonal and chemotherapy.Trastuzumab (Herceptin(R)) is available as an adjunct treatment for tumors which over-express the HER2/neu gene. Typically, metaplastic carcinomas of the breast do not express the estrogen or progesterone receptors and do not over-express the HER2/neu oncogene. As a result of this "triple negative" phenotype, such tumors tend to be more aggressive and are unlikely to respond to targeted therapy with Herceptin. The epidermal growth factor receptor HER-1/EGFR protein is expressed in the majority of metaplastic carcinomas and thus may serve as a potential therapeutic target for EGFR inhibitors such as gefitinib and cetuximab. The two cases we describe exemplify the aggressive nature of carcinosarcoma of the breast and support the findings that this tumor type does not express the common receptors found in other breast carcinomas. These case reports also emphasize the need for investigating the role for blockade of the HER-1/EGFR receptor with targeted therapies when found to be over-expressed in the primary tumor.
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PMID:Carcinosarcoma of the breast: two case reports and review of the literature. 1912 25

HER2 is an important predictive marker for response to trastuzumab and lapatinib in breast cancer. It is also a powerful prognostic marker in node-positive patients. Although standardized assays are used to help select patients for anti-HER2 therapy, there are no standardized criteria for assessing HER2 as a prognostic marker. Recent data using quantitative image analysis suggest that both high and low HER2 expression are associated with poor clinical outcome. Using the immunohistochemical scoring criteria currently recommended by the College of American Pathologists and American Society of Clinical Oncology to help select patients for trastuzumab, we evaluated HER2 protein expression in tumor tissue microarrays of 91 node-positive patients with invasive breast carcinoma treated with mastectomy and doxorubicin-based chemotherapy without trastuzumab and without irradiation with a median follow-up of 12.5 years. A wide range of HER2 expression (HER2 >or=1+) in the primary tumor was significantly associated with decreased locoregional recurrence-free survival (P=0.014), decreased disease-specific survival (P=0.001), and decreased overall survival (P=0.001). Even in the subset considered HER2 negative by current College of American Pathologists and American Society of Clinical Oncology guidelines, HER2=1+ was associated with worse outcome than HER2=0 in this patient cohort. The association between HER2 >or=1+ and worse outcome had the greatest statistical significance in the hormone receptor-positive subset of patients. These findings support the hypothesis that low-level HER2 expression may have significant clinical implications. Although the assessment of HER2 expression is most important for predicting response to anti-HER2 therapy, detection of low-level HER2 expression might also be useful in helping to select a more aggressive treatment regimen for patients ineligible for anti-HER2 therapy.
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PMID:Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. 1974 98

Male breast cancer (MBC) is considered as a rare disease comprising about 1% of all breast cancers. As compared to women breast cancer, MBC has some similarities and also some particularities related to age, comorbidities, breast volume, diagnostic delay, prognosis and survival. Modified radical mastectomy (MRM) with axillary dissection is the gold standard. Sentinel lymph node dissection is a promising option for early stages. Adjuvant radiation is proposed because of the high frequency of node involvement and central tumor location. In hormone receptor positive tumors tamoxifen remains the gold standard endocrine therapy because of the lack of data on aromatase inhibitors. Adjuvant chemotherapy can be proposed to high-risk patients while trastuzumab should be an option in breast cancer that overexpresses HER2. In the setting of considerable evolution in the management of women breast cancer, this review aimed to point out on the similarities and particularities of MBC and the future challenges to improve MBC outcome.
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PMID:[Male breast cancer: a review]. 1925 25


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