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)

Hereditary breast carcinomas that are attributable to BRCA1/2 mutations have their own morphological and immunohistochemical characteristics. BRCA1-associated carcinomas are poorly differentiated infiltrating ductal carcinomas that frequently show morphological features of typical or atypical medullary carcinoma. BRCA2-associated breast carcinomas tend to be of higher grade than sporadic age-matched controls. BRCA1tumors have been found to be more frequently estrogen receptor- and progesterone receptor-negative, and p53-positive than are age-matched controls, whereas these differences are not usually found in BRCA2-associated tumors. In addition, BRCA1- and BRCA2-associated breast carcinomas show a low frequency of HER2 expression. Most BRCA1 breast carcinomas are characterized by the expression of basal (myoepithelial) markers, such as cytokeratin 5/6 and or P-cadherin. These features could be used to distinguish patients who are likely to carry a BRCA1 or BRCA2 germline mutation, thus indicating which gene should be screened for first in families with a high incidence of breast and ovarian cancer.
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PMID:Histopathology of BRCA1- and BRCA2-associated breast cancer. 1653 Apr 20

The aggressiveness of meningiomas is unpredictable. HER2 represents a well-known prognostic factor in various tumors such as breast carcinomas. This work was designed to study HER2 protein expression and HER2 gene amplification in meningiomas and to evaluate their prognostic value. Frozen sections of 35 meningiomas were immunostained for HER2, estrogen receptor, progesterone receptor, E-cadherin, and MIB-1. Meningiomas immunostained for HER2 were further examined for the HER2 gene amplification by dual-color fluorescence in situ hybridization using probes for centromere 17 and 17q11.2-q12. Complete clinical information was obtained in all cases. The study included 15 atypical meningiomas, 3 anaplastic meningiomas, and 17 classic meningiomas. Five atypical/anaplastic meningiomas and 5 classic meningiomas of the whole 35 (28.5%) meningiomas expressed HER2 protein. This was considered as an overexpression in comparison with negative normal meninges. Fluorescence in situ hybridization demonstrated more HER2 gene copy in 4 of these 10 HER2-positive meningiomas. At equivalent histologic grading, meningiomas with HER2 overexpression exhibited similar immunohistochemical parameters of prognostic value than their HER2-negative counterparts; however, the rate of tumor recurrence was significantly higher in meningiomas with HER2 overexpression than in HER2-negative meningiomas. Conversely, HER2 amplification was not associated with recurrence. Some meningiomas exhibit HER2 protein overexpression in part induced by gene amplification. However, only HER2 overexpression could represent an independent prognostic factor in meningiomas.
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PMID:Prognostic value of HER2 expression in meningiomas: an immunohistochemical and fluorescence in situ hybridization study. 1656 15

Tetratricopeptide repeat domain 9 (TTC9) mRNA was drastically up-regulated by progesterone in progesterone receptor-transfected breast cancer cells MDA-MB-231. This up-regulation is coupled with progesterone-mediated growth inhibition and induction of focal adhesion. We have generated mouse polyclonal antibody against a predicted 222 aa TTC9 protein and identified a 25 kDa TTC9 protein that is widely expressed in human tissues, with the highest expression in the brain. Immunostaining and cell fractionation studies revealed that TTC9 is predominantly localized to the endoplasmic reticulum. The level of TTC9 protein in MCF-7 cells is regulated by various factors and chemical reagents including estrogen, progesterone, growth factors, ICI182,780, and p38 kinase inhibitor SB203580. Growth factor-induced TTC9 protein expression was inhibited by estrogen and abolished by ERK inhibitor PD98059. Though the function of TTC9 is not yet clear, the susceptibility of its protein level to biological and chemical agents suggests that TTC9 is a biologically significant protein.
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PMID:Identification of tetratricopeptide repeat domain 9, a hormonally regulated protein. 1667 94

We have previously reported that high grade and non-high grade ductal carcinoma in situ (DCIS) of the breast can be subdivided into 3 cell origin subtypes (luminal, basal/stem, and null), and that high grade DCIS is more frequently associated with basal/stem cell subtypes compared to non-high grade DCIS. Here we refine the relationships between these 3 subtypes and the expression patterns of estrogen receptor-alpha (ER-alpha), progesterone receptor (PR), HER-2/neu, and epidermal growth factor receptor (ERFR) in 53 cases of non-high grade and 46 cases of high nuclear grade DCIS. Using a panel of antibodies to ER-alpha, PR, HER-2/neu, and EGFR, along with cytokeratin (CK) markers (CK5/6, CK8, CK14, CK17, and CK18), we found that all 3 cell origin subtypes can express ER-alpha and PR, and their expression is higher in non-high grade DCIS than in high grade DCIS; the expression of HER-2/neu is associated with luminal subtype only in non-high grade DCIS, but can be seen in all 3 subtypes in high grade DCIS; the expression of EGFR is low and is present only in luminal cell subtypes in both high and non-high grade DCIS. Basal/ stem cell and null cell subtypes occur in younger patients in non-high grade DCIS compared to high grade DCIS. In conclusion, the expression patterns of ER-alpha, PR, HER-2/neu, and EGFR are markedly different in different cell origin subtypes of both high grade and non-high grade DCIS, suggesting that cell origin subtypes as well as nuclear grade contribute to the biological and molecular heterogeneity of DCIS.
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PMID:Expression patterns of ER-alpha, PR, HER-2/neu, and EGFR in different cell origin subtypes of high grade and non-high grade ductal carcinoma in situ. 1668 8

The role of beta-catenin in breast cancer and its prognostic value is controversial. The prognostic value had been assessed previously in a series of nonquantitative immunohistochemical studies with conflicting results. In efforts to clarify the relationship between beta-catenin protein expression and breast cancer prognosis, we have assessed a retrospective 600 case cohort of breast cancer tumors from the Yale Pathology archives on tissue microarrays. They were assessed using automated quantitative analysis (AQUA) with a series of array-embedded cell lines for which the beta-catenin concentration was standardized by an ELISA assay. The expression levels of the standard clinical markers HER2, estrogen receptor (ER), progesterone receptor (PR), and Ki-67 were also assessed on the same cohort. X-tile software was used to select optimal protein concentration cutpoints and to evaluate the outcome using a training set and a validation set. We found that low-level expression of membranous beta-catenin is associated with significantly worse outcome (38% versus 76%, 10-year survival, validation set log-rank P = 0.0016). Multivariate analysis of this marker, assessed in a proportional hazards model with tumor size, age, node status, nuclear grade, ER, PR, HER2, and Ki-67, is still highly significant with a hazard ratio of 6.8 (P < 0.0001, 95% confidence interval, 3.1-15.1). These results suggest that loss of beta-catenin expression at the membrane, as assessed by objective quantitative analysis methods, may be useful as a prognostic marker or may be part of a useful algorithm for prognosis in breast cancer.
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PMID:Quantitative in situ analysis of beta-catenin expression in breast cancer shows decreased expression is associated with poor outcome. 1670 78

We report a case of a 49-year-old Japanese woman diagnosed with breast carcinoma with osseous and cartilaginous metaplasia with a poor outcome. Histological examination revealed invasive ductal carcinoma with undifferentiated sarcomatous components including chondrosarcomatous areas. Osseous metaplasia was also noted in a very limited area. Neither axillary lymph node metastases nor vessel invasion were observed. Immunohistochemical examination was negative for estrogen receptor, progesterone receptor and HER2 overexpression. Stage II A T2N0M0 carcinoma was diagnosed postoperatively. Five months after the operation, she developed lung metastases. Although she received systemic chemotherapy, the lesions increased in number and grew rapidly. She died of pulmonary distress 5 months after relapse.
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PMID:A case of breast carcinoma with cartilaginous and osseous metaplasia. 1675 21

There is increasing evidence that different types of breast cancers are related to distinct risk factors. We analyzed the risk of breast cancer with respect to circulating insulin-like growth factor (IGF)-I, IGF-binding protein (IGFBP)-3, 17beta-estradiol, estrone, testosterone, androstenedione and sex hormone-binding globulin (SHBG), taking into consideration the characteristics of the tumors. Plasma hormone levels of 102 postmenopausal patients with breast cancer detected by mammography screening, and 102 matched controls were analyzed in relation to the histological type, the status of the estrogen receptor (ER), the progesterone receptor (PR) and the HER2 in the tumors. Significant positive associations were revealed between the IGF-I concentration and the overall risk of breast cancer (OR=3.1, 95% CI: 1.5-6.2), ER+PR+ breast cancer (OR=2.4, 95% CI: 1.1-5.4) and ER+PR- breast cancer (OR=4.3, 95% CI: 1.2-14.3) when the highest and the lowest ranges of IGF-I were compared. Significant associations were also found between the highest and the lowest quartiles of testosterone, resulting in OR=4.1 (95% CI: 1.8-9.4) for the risks of breast cancer and OR=5.8 (96% CI: 2.1-16.2) of ER+PR+ breast cancer. A synergy was seen between IGF-I and testosterone levels. When both plasma IGF-I and testosterone were in the highest quartile ranges, an OR=26.4 (95% CI: 1.6-426.5, p=0.021) was computed for breast cancer overall. No significant synergistic effects could be demonstrated with other parameters. There were significant, 2.5-fold (95% CI: 1.2-5.6), and 16-fold (95% CI: 2.0-133.5) increases in the overall risks of breast cancer and of ER+PR- breast cancer, respectively, when the highest and the lowest quartiles of IGFBP-3 were compared. No associations were found between any of the hormones and the risk of ER-PR- tumors. The increased prevalence of ER+ breast cancers in patients with higher levels of IGF-I, IGFBP-3 or testosterone implicate these hormones in the etiology of hormone-dependent breast cancer. Additional analyses specific for breast cancer subtypes may shed light on the value of hormone determinations for tailored chemoprevention.
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PMID:Elevated levels of circulating insulin-like growth factor-I, IGF-binding globulin-3 and testosterone predict hormone-dependent breast cancer in postmenopausal women: a case-control study. 1677

It has been proposed that cannabinoids are involved in the control of cell fate. Thus, these compounds can modulate proliferation, differentiation, and survival in different manners depending on the cell type and its physiopathologic context. However, little is known about the effect of cannabinoids on the cell cycle, the main process controlling cell fate. Here, we show that Delta(9)-tetrahydrocannabinol (THC), through activation of CB(2) cannabinoid receptors, reduces human breast cancer cell proliferation by blocking the progression of the cell cycle and by inducing apoptosis. In particular, THC arrests cells in G(2)-M via down-regulation of Cdc2, as suggested by the decreased sensitivity to THC acquired by Cdc2-overexpressing cells. Of interest, the proliferation pattern of normal human mammary epithelial cells was much less affected by THC. We also analyzed by real-time quantitative PCR the expression of CB(1) and CB(2) cannabinoid receptors in a series of human breast tumor and nontumor samples. We found a correlation between CB(2) expression and histologic grade of the tumors. There was also an association between CB(2) expression and other markers of prognostic and predictive value, such as estrogen receptor, progesterone receptor, and ERBB2/HER-2 oncogene. Importantly, no significant CB(2) expression was detected in nontumor breast tissue. Taken together, these data might set the bases for a cannabinoid therapy for the management of breast cancer.
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PMID:Delta9-tetrahydrocannabinol inhibits cell cycle progression in human breast cancer cells through Cdc2 regulation. 1681 34

The insulin-like growth factor receptor type 1 (IGF1R) is suggested to play important roles in cancer cell growth through cross-talk with hormone receptors and growth factor receptors. However, its clinical significance in breast cancers in vivo is still unclear. We examined immunohistochemically the expression of IGF1R, phosphorylated-AKT (pAKT) and phosphorylated-ERK1/2 (pERK1/2) using tissue microarray slides containing 150 cases of primary breast carcinoma. Their mutual correlation and correlation with the status of hormone receptors epidermal growth factor receptor and human epidermal growth factor receptor type 2 were also investigated. IGF1R overexpression was detected in 71 cases (47%), and was correlated with lower nuclear grade (P = 0.03), positive estrogen receptor (ER) and/or progesterone receptor status (P = 0.002). pERK1/2 expression, detected in 53 cases (35%), was correlated with positive ER (P < 0.0001) and lower nuclear grade (P = 0.014). pAKT expression, detected in 88 cases (59%), was not correlated with nuclear grade, hormone receptors status or other clinical parameters. Of the 71 IGF1R-overexpressing tumors, pERK1/2 expression was detected in 27 (56%) of 48 ER-positive cases but in only four (17%) of 23 ER-negative cases (P = 0.022). In contrast, pAKT expression was constantly (64% or higher) detected irrespective of hormone receptor status in IGF1R-overexpressing breast cancers. Taken together, these findings suggest that IGF1R overexpression might activate pERK1/2 and pAKT in hormone receptor-positive breast cancer, but activate only pAKT in hormone receptor-negative breast cancer.
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PMID:Alternative tyrosine phosphorylation of signaling kinases according to hormone receptor status in breast cancer overexpressing the insulin-like growth factor receptor type 1. 1682 99

Fine needle aspiration is an established diagnostic tool in breast carcinoma. Although the potential of using the same diagnostic aspirate material to provide additional cytomorphologic prognostic or predictive information has been investigated, no well-recognized, practical grading system has been established. Such system is necessary in guiding treatment, monitoring neoadjuvant chemotherapy effect and predicting outcome. We herein propose a new grading system, combining nuclear grade, cellular dyscohesion, and bare atypical nuclei to arrive at one cytoprognostic score. Cytoprognostic scores were compared with other known prognostic factors. Fine needle aspirations of breast diagnosed as adenocarcinoma from 55 patients were reviewed. The cytoprognostic score combined three features including nuclear grade (score 1-3), cellular dyscohesion (score 1-3), and bare atypical nuclei (score 0, 1). A cytoprognostic score of 3 and below was considered a low score, and a score of 4-7 was considered a high score. The cytoprognostic score was then compared to histologic grade, lymph node status, and expressions of estrogen receptor, progesterone receptor, Her2-Neu, Ki-67, and p53 in the subsequently excised tumor. A low cytoprognostic score predicted a low to intermediate grade carcinoma and a high score predicted an intermediate to high-grade carcinoma. A high cytoprognostic score also correlated with more positive lymph node metastasis, and poor expression of prognostic markers. In conclusion, cytoprognostic score is performed with ease and shows a great promise as a cost-effective way to predict biological behavior of breast carcinoma and guide clinical management.
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PMID:Proposed prognostic score for breast carcinoma on fine needle aspiration based on nuclear grade, cellular dyscohesion and bare atypical nuclei. 1685 Apr 93


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