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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)

Breast cancer is a heterogeneous malignancy; its age-specific incidence profile rises exponentially until menopause and increases more slowly thereafter, reflecting the superimposition of early-onset and late-onset breast cancer rates. While early-onset breast cancers largely represent inherited or early life transforming effects on immature mammary epithelium, late-onset breast cancers likely follow extended exposures to promoting stimuli of susceptible epithelium that has failed to age normally. Among stimuli thought to promote late-onset breast tumorigenesis are the altered extracellular matrix and secreted products of senescent fibroblasts; however, the extent to which these senescent influences exist within the aging breast remains unknown. Clinical observations and biomarker studies indicate that late-onset breast cancers grow more slowly and are biologically less aggressive than early-onset breast cancers, even when controlled for hormone receptor (e.g. estrogen receptor, ER) and growth factor receptor (e.g. HER2) expression, supporting the conclusion that the biology of breast cancer is age-dependent.
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PMID:Impact of aging on the biology of breast cancer. 1794 89

There is a long tradition for defining prognostic factors in breast carcinoma; the classic ones being lymphnode status, tumor size, malignancy grade, and hormone receptor status. More important are the detection of predictive factors, defined as factors in the tumor which predict the effect of a certain treatment. The hormone receptors are a classic example of predictive factors for determining whether patients should be offered endocrine treatment. New predictive factors are HER2 for predicting the effect of trastuzumab and TOP2A for predicting the effect of certain chemotherapies.
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PMID:[Prognostic and predictive factors for endocrine treatment in breast carcinoma]. 1795 80

Previous studies have shown conflicting results on prognostic significance of basal-like breast tumors, but hormone receptor is a confusing factor in most of the prognostic evaluations. We aimed to characterize the prognostic features of basal-like tumors without the influence of hormone receptor status in a series of hormone receptor-negative breast tumors. Using tissue microarray and immunohistochemistry methods, according to the expression of HER2 and basal markers (CK5/6, CK14, EGFR), we categorized 713 consecutive hormone receptor-negative invasive breast cancers into 3 subtypes: HER2 (HER2+), basal-like (HER2-, any basal marker+), and null (HER2-, all basal markers-). The HER2 phenotype was subdivided into pure-HER2 (HER2+, all basal markers-) and basal-HER2 (HER2+, any basal marker+) subgroups. Expression of p53, p63, vimentin, and BRCA1 was assessed immunochemically. Basal-like tumors showed significantly higher grade, more frequent recurrence, and higher expression of vimentin and p63 than HER2 and null phenotypes. Basal-HER2 phenotype had significantly younger mean age and expressed a higher level of p53 and vimentin like basal-like and/or HER2 phenotypes. However, unlike all the other hormone receptor-negative phenotypes, they highly expressed BRCA1. No significant difference was found in 5-year survival among basal-like and the other hormone receptor-negative phenotypes, except for basal-HER2, which showed poorer 5-year overall survival than basal-like tumors. In conclusion, although basal-like breast tumors have distinct clinicopathologic and immunohistochemical features, they have similar 5-year survival compared with the other hormone receptor-negative tumors including HER2 and null phenotypes. However, there exists a small group of hormone receptor-negative tumors expressing HER2 and basal markers simultaneously. This small group of tumors showed significantly poorer 5-year overall survival than basal-like breast tumors and might require different treatment strategy.
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PMID:Basal-HER2 phenotype shows poorer survival than basal-like phenotype in hormone receptor-negative invasive breast cancers. 1804 47

In budding yeast, telomeres, the ribosomal DNA array, and HM loci are transcriptionally silenced by chromatin complexes containing Sir proteins. Hek2, a protein containing three evolutionary conserved RNA-binding K-homology domains, was identified as a suppressor of telomeric silencing [telomeric position effect (TPE)]. To explore the mechanisms of Hek2p action in gene silencing, we examined its relationship with Sir proteins. This search revealed an epistatic interaction between HEK2 and SIR1 at telomeres. Both single mutations, sir1Delta and hek2Delta, enhanced TPE, whereas the effect of double mutation, sir1Delta hek2Delta, did not exceed that of the single mutations. The results of chromatin immunoprecipitation analysis demonstrate that the TPE enhancement observed in these mutants is associated with increased binding of Sir2 protein to telomeres. At the HMR locus, hek2Delta rescues the silencing defect caused by sir1Delta mutation and reverses the loss of Sir2p and Sir3p. These data suggest that the epistatic interaction of HEK2 and SIR1 reflects competition between telomeres and HMR for Sir2/3 factors where HEK2 acts to suppress silencing. Because chromatin immunoprecipitation analysis reveals the presence of Hek2p at a subtelomeric region and HMR, its silencing effects at these loci are likely direct. These observations suggest that HEK2 regulates the composition of Sir complexes at HMR and telomeres.
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PMID:Epistatic interaction between the K-homology domain protein HEK2 and SIR1 at HMR and telomeres in yeast. 1806 21

Breast cancer is a heterogeneous disease that encompasses several distinct entities with remarkably different biological characteristics and clinical behaviour. Currently, breast cancer patients are managed according to algorithms based on a constellation of clinical and histopathological parameters in conjunction with assessment of hormone receptor (oestrogen and progesterone receptor) status and HER2 overexpression/gene amplification. Although effective tailored therapies have been developed for patients with hormone receptor-positive or HER2+ disease, chemotherapy is the only modality of systemic therapy for patients with breast cancers lacking the expression of these markers (triple-negative cancers). Recent microarray expression profiling analyses have demonstrated that breast cancers can be systematically characterized into biologically and clinically meaningful groups. These studies have led to the re-discovery of basal-like breast cancers, which preferentially show a triple-negative phenotype. Both triple-negative and basal-like cancers preferentially affect young and African-American women, are of high histological grade and have more aggressive clinical behaviour. Furthermore, a significant overlap between the biological and clinical characteristics of sporadic triple-negative and basal-like cancers and breast carcinomas arising in BRCA1 mutation carriers has been repeatedly demonstrated. In this review, we critically address the characteristics of basal-like and triple-negative cancers, their similarities and differences, their response to chemotherapy as well as strategies for the development of novel therapeutic targets for these aggressive types of breast cancer. In addition, the possible mechanisms are discussed leading to BRCA1 pathway dysfunction in sporadic triple-negative and basal-like cancers and animal models for these tumour types.
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PMID:Triple negative tumours: a critical review. 1817 22

Breast cancer is the one of leading causes of cancer-related deaths in women within economically developed regions of the world. The heterogeneity of the natural history of breast cancer complicates patient management in that there is tremendous variability in response to treatment and for survival. More recently, several biomarkers (hormone receptor status and HER2 expression) have been added to the risk evaluation and therapeutic assessments. Evolving knowledge of molecular biology and newer techniques, such as genomics and proteomics, offer the potential to better define the biologic nature of the disease process, both for risk and therapy. This review discusses classical as well as new prognostic and predictive techniques. These are leading to a paradigm shift from empirical treatment to an individually tailored approach, which may soon become a realistic option for patients, based on specific molecular profiles.
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PMID:Implications of applied research for prognosis and therapy of breast cancer. 1824 13

The use of neoadjuvant chemotherapy prior to surgical resection for breast cancer is no longer restricted to patients with locally advanced disease. As preoperative treatment becomes more common, the question arises whether or not such therapy changes important tumor characteristics. The objective of our study is to compare histological grade, hormone receptor status, and HER2/neu expression pre- and post-therapy patients receiving preoperative neo-adjuvant chemotherapy. Forty patients status post-neoadjuvant treatment who had available archived pathologic material pre- and post-therapy were identified. Glass slides were reviewed retrospectively, and tumor grade, hormone receptor status, and HER2/neu expression were compared between the pre- and post-therapy specimens. No significant differences were noted between the pre- and post-specimens for two of the three parameters comprising the modified Bloom-Richardson grade, including degree of tubule formation (p = 0.062) and nuclear pleomorphism (p = 0.086). For mitotic activity, a decrease in score was observed between pre- and post-therapy specimens which was statistically significant (p = 0.021). However, there was no significant difference in the overall modified Bloom-Richardson grade (p = 0.118). Information was available regarding hormone receptor and HER2/neu status in 26 patients (65%). There was no significant difference between pre- and post-treatment specimens for hormone receptor status. However, there were more patients with HER2/neu overexpression after receiving neoadjuvant therapy (p = 0.027). Neoadjuvant therapy resulted in a significant decrease in mitotic count and an increase in the proportion of patients with HER2/neu overexpression. No significant changes were noted for the degree of tubule formation, nuclear pleomorphism, overall Bloom-Richardson score, and hormone receptor status. However, small sample size may be a limitation of these results.
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PMID:The effect of neoadjuvant chemotherapy on histologic grade, hormone receptor status, and HER2/neu status in breast carcinoma. 1824 53

The natural course of early breast cancer has changed as a result of the introduction of mammographic screening. The present aim was a prospective analysis of screen-detected and symptomatic operable breast cancers in the era of mammographic service screening. The mode of detection (screen-detected, symptomatic or interval cancer), the type of mammographic image and other characteristics (the invasive tumor size, histological tumor type, grade, nodal, hormone receptor and HER2 status and the presence of lymphovascular invasion) of 569 invasive breast cancers were studied. Screen-detected cancers were significantly more frequently of grade I, < 10 mm of size and node-negative (p < 0.001, respectively). Symptomatic/interval cancers were significantly more frequently of grade 3, >20 mm of size (p < 0.001), and exhibited lymphovascular invasion (p = 0.001). Screening-detection of the tumor favored breast-conserving surgery, sentinel lymph node biopsy and the avoidance of chemotherapy (p < 0.001). Cancers associated with casting-type calcifications on the mammogram were typically of ductal type (p = 0.043), of grade 2-3, estrogen receptor and progesterone receptor-negative and HER2-positive (p < 0.001). Interval cancers occurred significantly more often at a younger age and remained mammographically occult as compared with other cancers. Mammographic screen-detected cancers demonstrate more favorable prognostic features, and need less extensive treatment than symptomatic or interval cancers. The mammographic appearance of the tumor reflects its biological behavior, and this should be considered in the management optimization.
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PMID:Tumor characteristics in screen-detected and symptomatic breast cancers. 1834 32

The aim of the present study was to evaluate the effectiveness of fluorescence in situ hybridisation (FISH), as a screening test, in moderately- (G2) or poorly- (G3) differentiated breast cancers of the ductal (IDC) and lobular (ILC) histotypes and distant metastases. HER2 FISH was performed on 486 G2 and 477 G3 both of IDC and ILC histotypes and in 241 metastases. A significant difference in the HER2 amplification was observed between G2 (14.8%) and G3 (31.9%), with no difference according to the histotype. However, the rate of amplification increased to 36% in the G2/hormone receptor-negative cases as compared to 10.6% in the G2/receptor-positive cases (p<0.0001). HER2 was amplified in 17% of metastases with some differences depending on the location. These data suggest that the HER2 FISH analysis may be an effective screening test in breast cancer metastases and G3 tumors, irrespective of the hormone receptor status or presence of lymphovascular invasion.
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PMID:Fluorescent in situ hybridization as a screening test for HER2 amplification in G2 and G3 breast cancers of lobular and ductal histotype and metastases. 1842 87

This retrospective study analyzed risk factors influencing the time to development of brain metastases with the aim to facilitate the definition of a high-risk population among breast cancer patients. One hundred seventy-four breast cancer patients with brain metastases, treated with whole brain radiotherapy, were evaluated. Statistical analysis included hormone receptor status, HER2/neu status, tumour grading, tumour stage, young age at the time of diagnosis, adjuvant systemic treatment, palliative systemic treatment, metastatic sites (if brain metastases were not the first site of recurrence), and immunotherapy with trastuzumab. Time to development of brain metastases was significantly prolonged by systemic palliative treatment (p< or =0.0001) whereas high tumour grading (p< or =0.04) and trastuzumab therapy (p< or =0.04) significantly shortened this time span. Patients with the brain as first metastatic site, age>35 (p< or =0.001) and stage III (p< or =0.018) at the time of diagnosis had a significantly shorter time to development for brain lesions. These factors should be further validated by a prospective trial to identify a high-risk population amongst breast cancer patients and enable the development of screening programs for early detection.
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PMID:Factors influencing the time to development of brain metastases in breast cancer. 1848 73


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