Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.1 (ERK)
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Several reports have shown that a long delay between cutting sections and immunohistochemical (IHC) staining can decrease the IHC reaction intensity. However, systematic large-scale studies to investigate to what extent this problem may influence the outcome of translational research studies are lacking. In this study, we used a tissue microarray (TMA) approach to investigate the influence of slide age on comparisons between the results of IHC analyses for estrogen receptor (ER), progesterone receptor (PR), cyclin D1, HER2 (HercepTest), and E-cadherin and clinical outcome in a series of 522 breast cancer patients. Old TMA sections stored for 6 months at 4 degrees C and freshly cut sections were analyzed under exactly identical experimental conditions. As compared to results obtained on freshly cut sections, the frequency of positivity on old sections decreased from 65 to 46% for ER (P<0.0001), from 33 to 18.5% for PR (P<0.0001), from 16.3 to 9.6% for HER2 (P=0.0047), from 45.1 to 37.7% for cyclin D1 (P=0.10), and from 58.9 to 32.9% for E-cadherin (P<0.0001). Despite the lower fraction of positive cases, most associations between IHC data and tumor phenotype that were observed in fresh section analysis were also found when old section data were analyzed. The results confirm that slide aging has a great influence on the intensity of IHC staining in individual cases, but they also suggest that many clinicopathological associations can be detected if suboptimally processed sections are used for IHC.
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PMID:Influence of slide aging on results of translational research studies using immunohistochemistry. 1603 36

The major objective of this experiment was to determine whether the bovine placenta could be stimulated to secrete progesterone, since the bovine placenta secretes little progesterone when the corpus luteum is functional. Secondly, we wanted to determine whether reported abortifacients or progesterone or estrogen receptor antagonists affected bovine placental prostaglandin secretion. The ovine placenta secretes half of the circulating progesterone at day 90 of pregnancy and PGE2 appears to regulate ovine placental progesterone secretion. Calcium has been reported to regulate placental progesterone secretion in cattle. Diced 186-245-day placental slice explants from six Brahman and six Angus cows were incubated in vitro at 39.5 degrees C under 95% air: 5% CO2 at pH 7.2 in 5 ml of M-199 for 1 h in the absence of treatments and for 4 and 8 h in the presence of treatments. Treatments were: vehicle; R24571; compound 48/80; IP3; PGE2; CaCl2; cyclosporin A; lipopolysaccharide (endotoxin) from Salmonella abortus equi., enteriditis, and typhimurium; monensin; ionomycin; arachidonic acid; mimosine; palmitic acid; progesterone, androstenedione; estradiol-17beta; A23187; RU-486; or MER-25. Jugular and uterine venous plasma and culture media were analyzed for progesterone, PGE2 and PGF2alpha by radioimmunoassay (RIA). Plasma hormone data were analyzed by a One-Way Analysis of Variance (ANOVA). Hormone data in culture media were analyzed for breed and treatment effects by a Factorial Design (2 breeds, 2-range of days, 21 treatments) for ANOVA (2 x 2 x 21). Since hormone data secreted by placental tissue in vitro did not differ (P > or = 0.05) by breed or range of days of pregnancy, data were pooled and analyzed by a One-Way ANOVA. Concentrations of PGE2 in uterine venous blood were two-fold greater (P < or = 0.05) in Angus than Brahman cows. PGE2 and PGF2alpha in vehicle controls increased from 4 to 8h (P < or = 0.05), but not progesterone (P > or = 0.05) Progesterone in culture media treated with RU-486 increased (P < or = 0.05) at 4 and 8 h compared to vehicle controls and was not affected by other treatments (P > or = 0.05). Concentrations of PGE2 in media at 4 and 8 h were lower (P < or = 0.05) when compared to controls except treatment with PGE2 at 4 and 8h and RU-486 at 8h (P > or = 0.05). PGF2alpha was increased (P < or = 0.05) by RU-486 at 8h and no other treatment affected PGF2alpha at 4 or 8 h (P < or = 0.05). In conclusion, modulators of cellular calcium signalling pathways given alone do not affect bovine placental progesterone secretion at the days studied and progesterone receptor-mediated events appear to suppress placental progesterone, PGF2alpha, and PGE2 secretion in cattle. In addition, PGE2 does not appear to regulate bovine placental progesterone secretion when the corpus luteum is functional and bacterial endotoxin does not appear to affect bovine placental secretion of PGF2alpha or PGE2.
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PMID:Do calcium-mediated cellular signalling pathways, prostaglandin E2 (PGE2), estrogen or progesterone receptor antagonists, or bacterial endotoxins affect bovine placental function in vitro? 1528 56

Caveolin-1 and -2 (CAV1, CAV2) are closely linked genes localised to the fragile region of 7q31 (FRA7G), and loss of heterozygosity involving this region has been reported in breast cancer. Several studies have suggested that CAV1 is a negative regulator of HER2/neu signal transduction in vitro. However, the clinical significance of CAV1 in breast cancer has not yet been clarified. We examined quantitatively the mRNA levels of CAV1, CAV2 and HER2/neu in 162 cases of breast cancer using real-time PCR. Caveolin-1 and -2 protein expression was also examined by Western blotting and immunohistochemistry. We then evaluated for correlations between CAV1, CAV2 and HER2/neu gene expression and clinicopathologic factors in the 162 breast cancer cases. Results showed higher HER2/neu mRMA levels and lower CAV1 and CAV2 mRMA levels in breast cancer tissues than in corresponding normal tissues (P<0.001). Caveolin-1 and -2 protein expression levels were also suppressed in cancer tissues compared to normal tissues by Western blotting. Immunohistochemistry revealed that CAV1 and CAV2 proteins were abundantly expressed in mammary gland myoepithelial cells, but only weakly in ductalepithelial cells. Reduced CAV1 mRNA level was significantly associated with increasing tumour size (P=0.041), and negative oestrogen receptor status (P=0.021). There was also a significant association between low CAV2 mRNA level and negative progesterone receptor status (P=0.013), and between high HER2/neu mRNA level and negative hormonal receptor status (ER, P=0.029, PgR, P=0.019). While there was no relationship between HER2/neu and CAV1 mRNA levels, a significant association between CAV1 and CAV2 mRNA levels was observed (P<0.001). Our results indicated that CAV1 suppression correlated closely with that of CAV2 in breast cancer, that CAV1 level was inversely correlated with tumour size, and that CAV1 and CAV2 levels were correlated with hormonal receptor status. Therefore, CAV1 and CAV2 play an important role in tumour progression in breast cancer patients.
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PMID:Clinical significance of Caveolin-1, Caveolin-2 and HER2/neu mRNA expression in human breast cancer. 1530

Only 10 cases of lymphoepithelioma-like carcinoma of the breast have been reported in the literature. This report adds one more case to the published literature. A 62-year-old woman presented with a mass in her left breast on physical examination. The mammographic images showed a 3.0 cm, poorly defined mass in the upper outer quadrant. A biopsy was recommended. The gross specimen consisted of a 5 cm portion of breast parenchyma with no discrete tumor. On microscopic examination, the tumor was composed of sheets of epithelioid cells arranged as single cells or in cords partially obscured by a dense lymphocytic infiltrate. The epitheliod cells extensively expressed cytokeratin stain, but did not express E-cadherin. The lymphoid cells expressed L26 stain in the germinal centers, and CD3 stain in the T lymphocytes surrounding the germinal centers and in between tumor cells. In situ hybridization showed no evidence of Epstein-Barr virus infection in the tumor cells. An overall review of 11 cases shows that the disease is usually seen in older patients. In situ and invasive lobular component was reported in 36% of the cases. Eight of 11 were negative for E-cadherin, 36% were estrogen receptor-positive, 18% were progesterone receptor-positive, and all of them were HER2/neu negative. None of the reported cases have been associated with Epstein-Barr virus infection. Only two of the cases showed lymph node metastasis, and long-term follow-up in one of them showed good prognosis. In summary, lymphoepithelioma-like carcinoma of the breast is a tumor with a good prognosis that should be considered as a possible diagnosis in breast tumors with an intense lymphocytic infiltrate.
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PMID:Lymphoepithelioma-like carcinoma of the breast: report of a case mimicking lymphoma. 1549 40

We evaluated the signaling pathways involved in regulating vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, in response to natural and synthetic progestins in breast cancer cells. Inhibition of the phosphoinositide-3'-kinase (PI3-kinase) signaling pathway or the specificity protein-1 (SP-1) transcription factor abolished both progesterone- and medroxyprogesterone acetate (MPA)-induced VEGF secretion from BT-474 and T47-DCO)cells. Inhibitors of the MAPK kinase 1/2/MAPK and N-terminal jun kinase/MAPK signaling pathways blocked both progesterone- and MPA-induced VEGF secretion in BT-474 cells. However, these inhibitors blocked only progesterone-, but not MPA-induced VEGF secretion in T47-DCO cells. Inhibitors of PI3-kinase or SP-1 blocked both progesterone- and MPA-induced increases in VEGF mRNA levels in T47-DCO cells. The proximal SP-1 sites within the VEGF promoter were critical for progestin-dependent induction of VEGF. In contrast, MAPK inhibitors did not block the progesterone- or MPA-induced increases in VEGF mRNA in T47-DCO cells, suggesting that MAPK inhibitors decreased progesterone-induced VEGF secretion in T47-DCO cells by blocking posttranscriptional mechanisms. The MAPK kinase/ERK/MAPK-independent induction of VEGF mediated by MPA was associated with the PRB [progesterone receptor (PR) B] isoform of the PR in T47-DCO cells. None of the inhibitors tested reduced basal PR levels or abrogated PR-dependent gene expression from a reporter plasmid, indicating that loss of PR function cannot explain any of the observed effects. Because the PI3-kinase signaling pathway and SP-1 transcription factor play critical roles in progestin-dependent VEGF induction, these may be useful targets for developing antiangiogenic therapies to prevent progression of progestin-dependent human breast cancers.
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PMID:Ligand- and cell-specific effects of signal transduction pathway inhibitors on progestin-induced vascular endothelial growth factor levels in human breast cancer cells. 1552 72

Disseminated tumor cells (DTC) in bone marrow are independently related to poor outcome in patients with breast cancer. Phenotypic characterization of DTC may be useful to improve evaluation of the metastasizing potential of DTC and also to more accurately target aggressive tumor cells. DTC were screened in bone marrow aspirates from breast cancer patients by immunocytochemistry with an anticytokeratin (anti-CK) antibody (A45B/B3). Because the cell permeabilization and fixation required for intracellular CK staining is deleterious for mRNA, we used microaspiration to isolate single tumor cells stained with a monoclonal antibody directed against a membrane epitope, epithelial cell adhesion molecule (EpCAM), in CK-positive cases. Urokinase-type plasminogen activator receptor (uPAR) was quantified by real-time quantitative RT-PCR. The SKBR3 human breast cancer cell line was used to calibrate RT-PCR. A linear relationship was observed between the cycle threshold (Ct) of uPAR and 18S gene expression and SKBR3 cells spiked (1, 3, 7, 10 and 20) in control patient bone marrow. EpCAM-positive cells were aspirated in 21 out of 25 bone marrow specimens from breast cancer patients with CK-positive cells and uPAR mRNA expression was determined in 16 cases. A high level of uPAR mRNA in DTC was detected in 8 out of 16 patients (50%) and was associated with a more aggressive primary tumor phenotype (estrogen receptor [ER]-negative, progesterone receptor [PR]-negative or HER2-positive) (p = 0.01). We demonstrated that real-time quantitative RT-PCR was reliably adapted to phenotype analysis of isolated micrometastatic cells. A larger study would be useful to confirm the importance of uPAR to define higher risk subgroups of breast cancer patients with micrometastatic disease.
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PMID:Real-time quantitative PCR determination of urokinase-type plasminogen activator receptor (uPAR) expression of isolated micrometastatic cells from bone marrow of breast cancer patients. 1554 15

Multiple different oncogenes have been described previously to be amplified in breast cancer including HER2, EGFR, MYC, CCND1, and MDM2. Gene amplification results in oncogene overexpression but may also serve as an indicator of genomic instability. As such, presence of one or several gene amplifications may have prognostic significance. To assess the prognostic importance of amplifications and coamplifications of HER2, EGFR, MYC, CCND1, and MDM2 in breast cancer, we analyzed a breast cancer tissue microarray containing samples from 2197 cancers with follow-up information. Fluorescence in situ hybridizations revealed amplifications of CCND1 in 20.1%, HER2 in 17.3%, MDM2 in 5.7%, MYC in 5.3%, and EGFR in 0.8% of the tumors. All gene amplifications were significantly associated with high grade. HER2 (P < 0.001) and MYC amplification (P < 0.001) were also linked to shortened survival. In case of HER2, this was independent of grade, pT, and pN categories. MYC amplification was almost 3 times more frequent in medullary cancer (15.9%), than in the histologic subtype with the second highest frequency (ductal; 5.6%; P = 0.0046). HER2 and MYC amplification were associated with estrogen receptor/progesterone receptor negativity (P < 0.001) whereas CCND1 amplification was linked to estrogen receptor/progesterone receptor positivity (P < 0.001). Coamplifications were more prevalent than expected based on the individual frequencies. Coamplifications of one or several other oncogenes occurred in 29.6% of CCND1, 43% of HER2, 55.7% of MDM2, 65% of MYC, and 72.8% of EGFR-amplified cancers. HER2/MYC-coamplified cancers had a worse prognosis than tumors with only one of these amplifications. Furthermore, a gradual decrease of survival was observed with increasing number of amplifications. In conclusion, these data support a major prognostic impact of genomic instability as determined by a broad gene amplification survey in breast cancer.
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PMID:Prognostic relevance of gene amplifications and coamplifications in breast cancer. 1557 59

Grading of invasive ductal carcinoma of no special type using the Nottingham combined histologic grading system provides independent prognostic information. The prognostic utility of grading invasive lobular carcinomas, however, has not been fully elucidated. In addition, the relationship between grade in invasive lobular carcinomas and expression of predictive biomarkers is less certain. The purpose of this study was to correlate histologic grade in invasive lobular carcinoma with known prognostic and predictive markers. All primary resections for invasive mammary carcinomas diagnosed in Mount Sinai Hospital, Toronto, between the years 1996 and 2002 were reviewed (n=1053). Of these cases, 50 were pure invasive lobular carcinoma (incidence 4.7%). The median age at diagnosis was 64 years. These tumors were graded using the Nottingham combined histologic grading system and analyzed for estrogen receptor, progesterone receptor, HER2/neu and E-cadherin expression. Tumor grade was correlated with tumor size (P=0.03), and the American Joint Committee on Cancer nodal status (P=0.05). Assessment of the individual components of grade showed that the mitotic score was highly correlated with tumor size (P=0.02), lymph node positivity (P=0.02) and overall American Joint Committee on Cancer stage (P=0.01). Estrogen receptor and progesterone receptor were highly expressed irrespective of the grade of tumor. HER2/neu protein overexpression and E-cadherin protein expression was absent in all invasive lobular carcinomas studied. We conclude that pure invasive lobular carcinoma is uncommon and occurs predominantly in postmenopausal women. Increasing tumor grade is correlated with median tumor size and the American Joint Committee on Cancer nodal stage, but not correlated with the expression of estrogen receptor, progesterone receptor, E-cadherin or HER2/neu protein overexpression.
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PMID:Invasive lobular carcinoma: to grade or not to grade. 1560 82

Neoadjuvant therapy followed by breast-conserving surgery has become an acceptable option for patients with locally advanced breast cancer. Although a distinct survival benefit has not been demonstrated using this approach, several questions have been raised following such therapy including its effects on receptor status and tumor markers. The current study retrospectively reviews estrogen receptor (ER), progesterone receptor (PR), and HER2-neu status in 55 consecutive patients treated by neoadjuvant chemotherapy. Preoperative and postoperative tumor markers were available for 43 of the 55 patients (78%). The pathologic complete tumor response rate (pCR) for this group was 19 per cent (8/43). Of those patients who did not achieve a pCR (n = 35), a change in tumor markers was seen in 25.7 per cent (9/35) of patients. When compared to a control group not undergoing neoadjuvant therapy, a significantly higher percent change in marker expression was noted in the neoadjuvant group (25.7% vs 5.9%, P = 0.046). ER, PR, and HER2-neu status remain important prognostic indicators for breast cancer. Tumor markers are useful in planning adjuvant therapy regimens. In this review, nearly 19 per cent of patients achieved a pCR. In patients not achieving a pCR, one in four patients had at least one change in tumor marker status. This study demonstrates the importance of establishing receptor and marker status prior to neoadjuvant therapy, as many patients will achieve a pCR and make tumor analysis impossible. Postoperative marker studies should be performed given the possibility of a change in status. The clinical relevance of this data will require further long-term follow-up. Until such data becomes available, caution should be considered when basing adjuvant therapy regimens on preoperative tumor marker studies alone.
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PMID:Neoadjuvant chemotherapy for locally advanced breast cancer results in alterations in preoperative tumor marker status. 1837 98

Apolipoprotein E (APOE) polymorphism plays an important role in lipid metabolism. Preliminary evidence suggests that APOE genotype appears to be a risk factor for not only cardiovascular disease, but also Alzheimer's disease and cancer. We screened the APOE genotype in 290 breast cancer patients and 232 non-cancer controls and determined the relationship between APOE gene polymorphism and breast cancer in Taiwan. We found risk for breast cancer was associated with the APOE genotype (xi(2) = 8.652, p = 0.013). Carriers of the epsilon4 allele were more common in breast cancer cases than carriers of epsilon3 allele (p = 0.004, OR = 1.786, 95% CI: 1.197-2.664). In addition, the epsilon4 allele is also associated with HER2/neu negative status in breast cancer patients (p = 0.006, OR = 0.277, 95% CI: 0.111-0.693). No significant associations between APOE genotype and tumor grade, TN classification, progesterone receptor, estrogen receptor, lymphatic invasion, or recurrence of breast cancer were in evidence. These results suggest that the APOE epsilon4 allele may be a risk factor for breast cancer and correlates with HER2/neu negative status.
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PMID:Influences of apolipoprotein E polymorphism on the risk for breast cancer and HER2/neu status in Taiwan. 1583 Jan 39


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