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 clinical application of molecular markers in the diagnosis, staging, and management of breast cancer continues to expand. Although the use of molecular markers in local-regional disease does not approach the level of their application in the systemic management of breast cancer, a growing body of rature supports the potential for molecular and genetic factors in clinical decision making regarding the local-regional management of breast cancer. As with conventional clinical and histopathologic factors, data regarding molecular and genetic factors as they relate to local-regional relapse may be conflicting and are subject to the usual limitations of predominantly retrospective studies. There are, however, some consistent data suggesting associations between local-regional control of disease and several molecular markers, including hormone receptor status, HER2/neu, p53, proliferative markers, and others. Interpretation of these data and how to use this information in clinical practice remains challenging. The available rature regarding the use of genetic and molecular markers in the local-regional management of breast cancer is summarized in this review.
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PMID:Molecular and genetic markers in the local-regional management of breast cancer. 1238 91

Because of its biological heterogeneity and wide spectrum of responsiveness to different treatments, breast cancer is a complex disease of difficult clinical management. Over the past several years, knowledge of the molecular mechanisms regulating normal and aberrant cell growth leading to cancer has been enhanced. These advances have enabled the identification of an increasing number of surrogate biomarkers, which have been correlated with prognosis or used as predictors of response to specific treatments. Axillary nodal status, age, tumor size, pathologic grade, and hormone receptor status are the established prognostic and/or predictive factors for selection of adjuvant treatments. The role of new biomarkers, such as p53, HER2/neu, angiogenesis, and the proliferation index value, is promising; however, the clinical value of their determination must be provided by prospective clinical studies.
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PMID:Prognostic and predictive indicators in operable breast cancer. 1263 83

Tumors of thyroid follicular cells provide a very interesting model to understand the development of human cancer. It is becoming apparent that distinct molecular events are associated with specific stages in a multistep tumorigenic process with good genotype/ phenotype correlation. For instance, mutations of the gsp and thyroid-stimulating hormone receptor genes are associated with benign hyperfunctioning thyroid nodules and adenomas while alterations of other specific genes, such as oncogenic tyrosine kinase alterations (RET/PTC, TRK) in papillary carcinoma and the newly discovered PAX8/peroxisome proliferator-activated receptor gamma rearrangement, are distinctive features of cancer. Although activating RAS mutations occur at all stages of thyroid tumorigenesis, evidence is accumulating that they may also play an important role in tumor progression, a role that is well documented for p53. Environmental factors (iodine deficiency, ionizing radiations) have been shown to play a crucial role in promoting the development of thyroid cancer, influencing both its genotypic and phenotypic features. It is possible that the follicular thyroid cell has unique ways to respond to DNA damage. Similarly to leukemia or sarcomas (and unlike most epithelial cancers), numerous specific rearrangements are being discovered in thyroid cancer suggesting preferential activation of DNA repair instead of cell death programs after environmentally induced genetic alterations.
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PMID:Molecular pathobiology of thyroid neoplasms. 1266 46

E1AF is a transcription factor involved in regulation of several metastasis-associated genes, and is associated with overexpression of HER2/neu. We were unable to find a clear prognostic value of E1AF expression in human breast cancer. Furthermore, no association of E1AF levels with HER2/neu mRNA levels, hormone receptor status, histological grade, tumor size, or lymph node involvement was found.
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PMID:E1AF expression levels are not associated with prognosis in human breast cancer. 1277 89

Adjuvant endocrine therapy reduces the risk of relapse and death from early stage hormone receptor positive breast cancer. However, tamoxifen is only partially effective because of the development of tumor resistance. Aromatase inhibitors (letrozole, anastrozole and exemestane) are also prone to the development of resistance but the pharmacologic action (estrogen deprivation) is distinct and so different mechanisms may be responsible. The problem of endocrine resistance can be directly studied in patients by examining the relationship between predictive tumor biomarkers and clinical outcome. In an example of a prospectively planned biomarker study, tumor samples were examined from a randomized trial of neoadjuvant endocrine treatment in which letrozole proved more effective than tamoxifen in terms of the rate of breast conservation and tumor regression. Interestingly letrozole was more effective at all levels of ER expression and was particularly more efficacious than tamoxifen for tumors that expressed HER1 and/or HER2 (with ER). This suggests that HER1/2 predicts primary tamoxifen resistance and relative sensitivity to potent estrogen deprivation, perhaps because HER1/2 signaling promotes the partial agonist effects of tamoxifen. A Phase 2 study of neoadjuvant letrozole is now underway to focus on gene expression profiling as a mechanism to further investigate the transcriptional programs that underlie resistance and sensitivity to estrogen deprivation. Expression profiles taken at baseline and after 1 month of therapy reveal dramatic reductions in the expression from genes responsible for DNA replication and synthesis, cell cycle progression, suppression of apoptosis and tissue invasion. When enough profiles have been generated it should be possible to detect complex interaction patterns that correctly reclassify ER+ disease into treatment responsive and resistant categories with high probability.
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PMID:Neoadjuvant comparisons of aromatase inhibitors and tamoxifen: pretreatment determinants of response and on-treatment effect. 1462 25

Secretory carcinomas (SCA) are distinguished from infiltrating ductal carcinomas (IDC) of the breast by their characteristic histomorphology and more favorable prognosis and by the expression of a chimeric tyrosine kinase that is encoded by the ETV6-NTRK3 fusion gene. On this basis, we evaluated 13 SCAs (12 of them with ETV6-NTRK3 gene fusion) by molecular and immunohistochemical (IHC) methods. DNA was obtained from 8 of 13 microdissected SCAs and was analyzed for genetic alterations (GA) by comparative genomic hybridization (CGH). IHC staining was performed for estrogen receptor (ER), progesterone receptor (PR), HER2/neu, and Ki-67 (MIB1) in all 13 cases. Molecular and immunohistochemical results in SCAs were compared with previous data regarding immunohistochemical and molecular characteristics of IDCs. An average of 2.0 GAs (range: 0 to 6) were detected, including recurrent gains of chromosome 8q (37.5%) and 1q (25%) and losses of 22q (25%). Four of 13 (31%) SCAs were positive for ER, and 2 were positive for PR. The mean MIB1-labeling index was 11.4% (range: <1 to 34%). Her-2/neu protein overexpression was detected in 2 cases, including 1 with strong (score 3+) and 1 with weak HER2/neu expression (score 2+). Fluorescence in situ hybridization analysis of the latter case showed no evidence of HER-2/neu-gene amplification. Compared with previous findings in IDCs, SCAs are characterized by a relatively low number of GAs, a low proliferative rate, infrequent HER2/neu protein overexpression, decreased steroid hormone receptor expression, and expression of ETV6-NTRK3 fusion gene. These results support the hypothesis that SCAs have immunohistochemical and genetic features that distinguish them from IDCs of the usual type.
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PMID:Secretory carcinoma of the breast: a distinct variant of invasive ductal carcinoma assessed by comparative genomic hybridization and immunohistochemistry. 1469 16

Although fine-needle aspiration cytology is a routine procedure for the diagnosis of breast carcinoma, cytologic specimens have rarely been used for evaluation of hormone receptor status and HER2/neu overexpression. In order to compare the biological markers on cytology and on histology, routinely fixed smears of 110 primary breast carcinomas were immunostained for estrogen receptor (ER), progesterone receptor (PgR), and HER2/neu by automated immunostainer and the results were compared with the corresponding histologic sections. ER was expressed in 76 of 110 (69%) cases and PgR was expressed in 51 of 110 (46%). Overexpression of HER2/neu was observed in 30 of 110 (27%) cases. Concordance between cytology and histology was 98% for ER, 95% for PgR, and 100% for HER2/neu. There was no false positive result on smears. Diagnostic pitfalls in determination of hormone receptor status on smears included intratumoral heterogeneity and presence of mucin.
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PMID:Hormone receptor status and HER2/neu overexpression determined by automated immunostainer on routinely fixed cytologic specimens from breast carcinoma: correlation with histologic sections determinations and diagnostic pitfalls. 1504 60

Breast cancer represents a major health problem, with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade, in spite of an increasing incidence, breast cancer mortality has been declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. Better knowledge of breast cancer biology now allows the cosmetic, physical and psychological consequences of radical mastectomy to be spared in the majority of breast cancer patients. Use of the sentinel node technique is rapidly expanding and this will further reduce the extent and the consequences of surgery. Several clinico-pathological factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse. Nodal status, tumour size, tumour grade and age are accepted universally as important factors to define risk categories. Newer factors such as uPA/PAI-1, HERer2-neu, proliferative indices and gene expression profile are promising and will allow better discrimination between patients at different risk. Endocrine manipulation with tamoxifen, ovarian ablation or both is the preferred option in the case of endocrine-responsive tumours. Tamoxifen administered for 5 years is the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen, with a different safety profile. At present, anastrozole can be used in the adjuvant setting in cases of tamoxifen intolerance or toxicity. Chemotherapy is the treatment of choice for steroid receptor-negative tumours. Polychemotherapy is superior to single agents and anthracycline-containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four of CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. The taxanes have been approved for adjuvant therapy in the USA, while European approval is pending. Combined endocrine-chemotherapy is the standard adjuvant treatment in high-risk patients with endocrine-responsive tumours. Endocrine manipulation is usually administered after completion of the chemotherapy programme. For HER2-neu overexpressing tumours, several rapidly accruing trials are exploring the potential additive effect of trastuzumab, a monoclonal antibody directed against the extramembrane portion of the HER2 receptor. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer, with increased rates of breast-conserving surgery. A proportion of patients achieve a pathological complete response and these patients have significantly better long-term outcomes. Twenty-five to forty percent of breast cancer patients develop distant metastases. At this stage the disease is incurable; however, treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In the case of hormone receptor positivity and in the absence of visceral, life-threatening disease, endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure anti-oestrogens and progestins. Aromatase inhibitors are the most active agents, but the choice and the sequence of endocrine therapies are also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in cases of receptor-negative tumours, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation, and this approach should be recommended in young patients with good performance status and visceral disease. On the other hand, single agents have a better tolerability profile and should be tand should be the treatment of choice when a careful balance between activity and tolerability is needed. For HER2-neu positive tumours, the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone in terms of both response rates and survival. Other useful palliative treatments include bisphosphonates for the control of metastatic bone disease and radiotherapy for painful bone lesions or local relapses.
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PMID:The curability of breast cancer and the treatment of advanced disease. 1510 48

Genetic events underlying the pathogenesis of breast cancer have been studied extensively and several clinically significant markers have been identified. For example, amplification and overexpression of the ERBB2 oncogene is associated with poor prognosis in breast cancer and ERBB2 serves as a target for antibody-based therapy. Current knowledge on the pathogenesis of male breast cancer (MBC) is limited. The purpose of our study was to investigate the potential relevance of a series of genes known to be amplified in female breast cancer (FBC) in a the development and pathogenesis of MBC. To this end, we applied fluorescence in situ hybridization and immunohistochemistry to the analysis of 128 breast tumors from males. Amplification of ERBB2, MYC, PPM1D and ZNF217 was detected rarely (1-2% of tumors) indicating a considerably lower amplification frequency than in FBC. CCND1 amplification was observed in 12% of cases, being in good concordance with findings from FBC. In addition, CCND1 overexpression was detected in 63% of tumors and was associated with ER positivity (p < 0.0001). Our results indicate distinct differences in the genetic basis of MBC and FBC and suggest that marked differences exist in the pathogenesis of these diseases. The lack of ERBB2 involvement was especially unexpected and implies that ERBB2-targeted therapies are unlikely to be beneficial in MBC. Furthermore, the high frequency of hormone receptor positivity and the association between ER positivity and CCND1 overexpression supports the notion that hormonal regulation is likely to be essential for the development of MBC.
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PMID:Frequent amplification and overexpression of CCND1 in male breast cancer. 1530 Aug 11

To optimize patient management in breast cancer a number of factors are considered, including hormone receptor and HER2 status. A feasible approach for women with less aggressive, estrogen receptor/HER2-positive metastatic breast cancer is to consider trastuzumab (Herceptin; F. Hoffmann-La Roche, Basel, Switzerland) combined with endocrine therapy. Randomized clinical trials are ongoing to assess the combination of trastuzumab with aromatase inhibitors. In patients with aggressive HER2-positive metastatic breast cancer, trastuzumab/chemotherapy combination regimens are warranted. When administered first line in combination with a taxane, trastuzumab improves all clinical outcome parameters, including survival, in such patients. Trastuzumab adds little to the toxicity profile of taxanes, and trastuzumab combination therapy is associated with improvements in quality of life when compared with chemotherapy alone. There is encouraging evidence of improved efficacy when trastuzumab is combined with other cytotoxic agents with proven single-agent activity in breast cancer, including capecitabine (Xeloda; F. Hoffmann-La Roche), gemcitabine, and vinorelbine. Trastuzumab is also being investigated as part of triplet drug regimens. Trastuzumab has good single-agent activity in first-line therapy. This is of relevance to women with HER2-positive disease who are not suitable for, or do not wish to receive, cytotoxic chemotherapy. The benefits noted with trastuzumab-containing regimens were documented in clinical trials where trastuzumab was given until disease progression. A further rationale exists to continue trastuzumab beyond progression. Data from retrospective reviews indicate that this strategy is feasible.
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PMID:Maximizing clinical benefit with trastuzumab. 1549 Mar 73


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