Cases were scored by two pathologists on a percentage basis and then converted to binary scores (positive or negative) on the basis of a bimodal distribution. RESULTS. Strong expression of met was found in 20 invasive ductal breast tumor School of Medicine, New Haven, Connecticut. specimens (22%). The 5-year survival of patients whose tumors showed decreased 2 Departments of Epidemiology and Nutrition, met expression was 89%, in contrast to a 52% 5-year survival rate in patients whose Harvard School of Public Health, Boston, Mas-tumors expressed met (P Å 0.008). This trend also was observed in patients without sachusetts. lymph node metastases at presentation, in whom met negative patients had a 95% 3 Division of Molecular Medicine and Genetics, 5-year survival compared with only 62% for met positive patients (P Å 0.006) University of Michigan Medical Center, Ann Multivariate analysis using the Cox proportional hazards model showed met ex-Arbor, Michigan. pression to be an independent predictor of survival, with a predictive value nearly equivalent to that associated with lymph node status. CONCLUSIONS. The authors conclude that expression of met in patients with inva-sive ductal carcinoma of the breast is a strong, independent predictor of decreased survival and may be a useful prognostic marker with which to identify a subset of patients with more aggressive disease. may be an example of such a marker. SF/HGF is a mesenchymal cell-School of Medicine, 310 Cedar St., New Haven, derived protein that dissociates epithelial cell colonies by causing a CT 06510. breakdown of intercellular junctions, scattering contiguous sheets of cells, and appears to modulate cell motility and invasion. 3-8 The c
Beyond depth of invasion, there are very few prognostic markers to predict outcome in melanoma. It has been shown recently that the -catenin oncogene is mutated or shows altered subcellular localization suggesting that activation of -catenin mediated signaling plays a role in oncogenesis. We hypothesize that assessment of activated -catenin, as detected by a phospho-specific antibody, may be useful to predict outcome in melanoma. We use immuno-histochemical analysis of -catenin and phospho--catenin, first to verify the specificity of the phospho--catenin antibody and then to assay expression in a tissue microarray-based study. The subcellular localization of -catenin is membranous in some cases and cytoplasmic and nuclear in others. We validate the specificity of a ser33/37/thr41 phospho--catenin antibody in transfected cells and show that the expression is almost exclusively localized to the nucleus in both cultured cells and human tissue. Evaluation of both total and phospho--catenin antibodies showed that cytoplasmic/nuclear staining was more common in primary lesions, whereas nuclear phospho--catenin was more common in metastatic lesions. High levels of nuclear phospho--catenin are associated with significantly worse overall survival (51% vs. 25% overall survival at 5 years, p ؍ 0.046). These results suggest that phosphospecific antibodies to -catenin define a unique subset of cases and that monitoring of phospho--catenin expression may be useful for assessing prognosis in malignant melanoma.
-Catenin-mediated signaling can be constitutively activated by truncation or mutation of serine and threonine residues in exon 3.
BACKGROUND It has been shown that receptor tyrosine kinases (RTKs) predict outcome in patients with breast carcinoma. Although RTKs are a large family, HER‐2, epidermal growth factor receptor (EGFR), Met (hepatocyte growth factor receptor), and others all have shown the ability to predict outcome. However, it remains unclear whether these markers are defining the same subpopulation of patients with breast carcinoma. In this study, the authors attempted to determine the correlation between RTKs on the basis of their ability to stratify a population according to outcome. METHODS The authors used tissue microarray technology to study 324 patients with lymph node negative breast carcinoma who had 20–40 years of follow‐up. Expression was assessed using immunohistochemical stains for Met, EFGR, fibroblast growth factor receptor (FGFR), and HER‐2. Expression levels were assessed by two observers, and correlations were analyzed. Standard pathology information, including tumor size, nuclear grade, Ki‐67 receptor status, and estrogen and progesterone receptor expression levels, also was collected. RESULTS RTK expression in the study cohort revealed two strong correlations. Specifically, HER‐2 and EGFR showed similar expression patterns (P < 0.0001), and Met cytoplasmic domain and FGFR cytoplasmic staining showed similar expression patterns (P < 0.0001), but no correlation was found between the two groups. Of these RTKs, only high levels of Met cytoplasmic domain showed significance as a prognostic marker defining a shortened survival compared with the rest of the population (P = 0.0035; relative risk, 2.04). In the same group of patients, HER‐2, hormone receptor status, and other RTK family receptors were not correlated with outcome. In multivariate analysis, only Met cytoplasmic domain and tumor size showed independent predictive value. CONCLUSIONS The current results indicate that the cytoplasmic domain of Met shows a unique staining pattern and defines a set of patients unique from the set of patients defined by overexpression of HER‐2, EGFR, or hormone receptors. Furthermore, this group of patients is associated tightly and independently with worse outcome. Cancer 2003;97:1841–8. © 2003 American Cancer Society. DOI 10.1002/cncr.11335
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