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: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

p27(Kip1) (p27), a cyclin-dependent kinase inhibitor, has an important role in the progression of cells from G(1) into S phase of the cell cycle. p27 may act as a tumor suppressor, and several reports suggest that loss of its expression in breast carcinoma is related to tumor progression and poor prognosis. We evaluated p27 immunohistochemical expression in 512 consecutive cases of breast carcinoma with 9 years of median-term follow-up. p27 expression was heterogeneous and frequently less intense than in normal cells. Low p27 expression (<50% of reacting cells) was associated with grade III tumors, N0 status, estrogen receptor-negative status, and low cyclin D1 expression. In the whole series of cases, p27 expression did not predict outcome. In node-negative cases (249 patients), high p27 expression indicated poor prognosis. p27 was not prognostically relevant in the group of 223 patients with pT1 disease or in the group of 154 patients <50 years of age. We also investigated the prognostic value of the combined expression of p27 and cyclin D1, but no differences in survival were seen in this bivariate analysis.
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PMID:p27(kip1) expression in breast carcinomas: an immunohistochemical study on 512 patients with long-term follow-up. 1086 99

Alternative splicing of CD44 and aberrant levels of soluble CD44 protein in the serum of cancer patients has been correlated to tumor progression and metastasis. To examine the clinical value of CD44 serum levels (sCD44) in ovarian cancer we determined concentrations of the soluble, variable isoforms sCD44std, sCD44v5 and sCD44v6 with a sensitive ELISA. Pre-operative serum samples from 66 patients with histologically diagnosed invasive disease as well as sera taken from 40 healthy blood donors were analyzed. In sera of ovarian cancer patients we detected elevated concentrations of overall CD44 serum levels represented by sCD44std (p=0.001), but decreased levels of the specific isoforms CD44v5 (p=0.0002) and v6 (p=0.0001). This is the first report demonstrating that ovarian cancer patients with pelvic lymph node metastasis at the time of diagnosis showed specifically elevated sCD44v6 (p=0.073) serum concentrations in comparison to patients without lymph node involvement, whereas overall sCD44 serum levels did not differ. Decreased serum levels of sCD44v5 were found in progesterone receptor-positive tumors (p=0. 059) and postmenopausal patients (p=0.032). Increased concentrations of sCD44v6 were detectable in estrogen receptor-positive tumors but not significantly (p=0.138). Serum CD44v5 levels were associated with shortened relapse-free survival time. No association was found between serum CD44 isoforms and the classical clinicopathological parameters stage and grading or overall survival. CD44 splice variants are possibly involved in a complex interaction with the hormonal environment during tumorigenesis and metastasis of ovarian cancer.
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PMID:Soluble CD44 splice variants and pelvic lymph node metastasis in ovarian cancer patients. 1102 31

The ligands, receptors and related signaling proteins of the insulin-like growth factor family are involved in the regulation of breast-cancer cell growth. We investigated the expression pattern of insulin-like growth factor-I receptor (IGF-IR), insulin receptor (IR) and insulin receptor substrate-1 (IRS-1), a core downstream signaling protein, in 69 primary breast-cancer specimens of different grades and in 21 control tissues by immunohistochemistry. In addition, cell proliferation (percentage of Ki67(+) nuclei) and estrogen receptor (ER) expression were determined. IGF-IR, IRS-1 and IR were expressed mainly in epithelial cells. IRS-1 and IGF-IR were expressed at high levels in control tissues and in well and moderately differentiated carcinomas but at low levels in poorly differentiated breast cancers. IR expression did not show a significant correlation with the differentiation grade of the tissues investigated. Statistical analysis (ROC analysis for tumor grade) demonstrated that down-regulation of IGF-IR and IRS-1 correlated better with tumor progression than reduction of ER expression or increase in cell proliferation, IGF-IR showing the best correlation, followed by IRS-1 and, less significant, ER and Ki67. Our findings clearly show that progression of breast cancer is accompanied by a reduction of IGF-IR/IRS-1 expression and that IGF-IR/IRS-1 expression inversely correlates with high proliferation rate in dedifferentiated breast cancers. The strong correlation of IGF-IR and IRS-1 down-regulation with tumor progression suggests the use of IGF-IR and IRS-1 as a novel set of marker proteins for tumor grading.
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PMID:Down-regulation of insulin-like growth factor-I receptor and insulin receptor substrate-1 expression in advanced human breast cancer. 1110 95

Angiogenesis is essential for tumor growth and metastasis. It is regulated by numerous angiogenic factors, one of the most important being vascular endothelial growth factor (VEGF). Recently, VEGF-C, a new VEGF family member, has been identified that binds to the tyrosine kinase receptors flt-4 [VEGF receptor (VEGFR) 3] and KDR (VEGFR2). Although the importance of VEGF has been shown in many human tumor types, the contribution of VEGF-C and its primary receptor flt-4 to tumor progression is less well understood. We have therefore measured the level of VEGF-C, flt-4, and KDR mRNA by RNase protection assay and the pattern of VEGF-C expression by immunohistochemistry in 11 normal breast tissue samples and 61 invasive breast cancers. No significant difference in VEGF-C expression was observed between normal and neoplastic breast tissues (P = 0.11). There was a significant correlation between VEGF-C and both flt-4 (P = 0.02) and KDR (P = 0.0002), but no association was seen between VEGF-C and either lymph node status (P = 0.66) or number of involved nodes (P = 0.88), patient age (P = 0.83), tumor size (P = 0.20), estrogen receptor status (P = 0.67), or tumor grade (P = 0.35). No significant relationship was present between VEGF-C and vascular invasion (P = 0.30), tumor vascularity (P = 0.21), VEGF-A (P = 0.62), or thymidine phosphorylase expression (P = 1.00). VEGF-C was expressed predominantly in the cytoplasm of tumor cells, although occasional stromal components including fibroblasts were also positive. We could demonstrate no association between lymph node metastasis and either VEGF-C (P = 0.66) or flt-4 (P = 0.4). However, we did observe a significant loss of the long but not the short isoform of flt-4 in tumors compared with normal tissues (P = 0.02 and P = 0.25, respectively), and this difference was largely accounted for by the reduction of long flt-4 in node-positive tumors. These findings strongly support a role for VEGF-C/flt-4 signaling in tumor growth by enhancement of angiogenesis and/or lymphangiogenesis and suggest that differential regulation of these processes may be controlled via flt-4 isoform transcription. They further suggest that the measurement of flt-4 isoform expression may identify a patient group that is likely to have node-positive disease and therefore benefit from additional treatment and also emphasize an additional ligand interaction that could be exploited by anti-VEGFR therapy.
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PMID:The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. 1110 44

Thymidylate synthase (TS) is a crucial target for 5-fluorouracil (5-FU) in the de novo pathway of pyrimidine synthesis, which is necessary for DNA synthesis. Thymidine kinase (TK) plays a key role in the complementary or alternative salvage pathway of pyrimidine synthesis in acute or pathological tissue stress. In the present study, the activity levels of TS and TK were determined in 257 primary breast tumors of patients who received tamoxifen as first-line systemic therapy after diagnosis of advanced disease. In 155 (60%) responding patients, the median response duration was 23 months for tumors with low TK activity, 15 months for tumors with intermediate TK activity, and 13 months for tumors with high TK activity (P = 0.003). In Cox multivariate analysis corrected for classical predictive factors including estrogen receptor and progesterone receptor, patients with intermediate and high levels of TK activity in their tumors showed a rapid disease progression (P = 0.0002) and an early death (P = 0.002) after start of tamoxifen treatment. Tumor TS activity levels were not significantly associated with the efficacy of tamoxifen treatment. In 121 patients who became resistant to tamoxifen or additional endocrine treatments and who received 5-FU-containing polychemotherapy, tumor TK activity was not significantly related to the efficacy of chemotherapy. Of the 13 patients with low tumor TS activity, only 1 (8%) responded favorably, whereas 46% (43 of 93) of those with intermediate and 73% (11 of 15) of those with high TS activity responded (P = 0.001). In Cox multivariate regression analysis in which TS was the only significant variable, intermediate and high TS activities were associated with a slow disease progression (P = 0.005) and prolonged survival (P = 0.016) on chemotherapy. In conclusion, for patients with recurrent breast cancer, high tumor TK activity is a significant marker of poor clinical outcome on tamoxifen therapy. Elevated tumor TS activity predicts a favorable outcome for 5-FU-containing polychemotherapy when applied after tumor progression on endocrine therapy.
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PMID:Thymidine kinase and thymidylate synthase in advanced breast cancer: response to tamoxifen and chemotherapy. 1124 45

We report herein the case of a 40-year-old man with grade II invasive ductal carcinoma of the breast (pT1, pN0, M0: stage I) in whom a recurrence developed shortly after completion of a 2-year course of tamoxifen and 5-fluorouracil therapy following a mastectomy. Although the metastatic tumor was estrogen receptor-positive, hormone therapy combined with chemotherapy had no significant effect on tumor growth, and the patient died from disseminated tumors 2 years 6 months after completion of the adjuvant therapy. It is noteworthy that the circulating estradiol level increased from 18.0 to 892.3 pg/ml during the period of tumor progression and dissemination. We interpret these findings as an indication of high aromatase activity in the metastatic tumors. We suggest that extending tamoxifen treatment to 5 years or longer be recommended for the standard adjuvant hormone therapy of male breast cancer to prevent the early recurrence of hormone-responsive disease.
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PMID:Tamoxifen-failed male breast cancer with a high level of circulating estrogen: report of a case. 1129 9

Previous studies indicated that a new member of the human kallikrein (KLK) gene family, KLK4, was expressed in prostate, breast, and endometrial carcinoma cell lines and may have potential as a tumor marker. The aim of this study was to examine the expression of KLK4 in the normal ovary and ovarian tumors of different histology, stage, and differentiation and to determine its association with ovarian tumor progression. Using reverse transcription-PCR, Southern blot, and densitometry analyses, we found the level of KLK4 expression was higher in late stage serous (SER) epithelial-derived ovarian carcinomas than in normal ovaries, mucinous epithelial tumors, and granulosa cell tumors. KLK4 was highly expressed in all of the SER ovarian carcinoma cell lines (eight of eight), SER epithelial carcinomas (11 of 11), and two adenomas, whereas it was expressed at a lower level (or not at all) in normal ovaries (four of six), mucinous epithelial tumors (three of four), endometrioid carcinomas (four of five), clear cell carcinomas (two of three), or granulosa cell tumors (three of six). Of particular interest, KLK4 mRNA variants were detected in SER ovarian carcinoma cell lines and primary cultured ovarian tumor cells, but they were not present in normal ovaries. In situ hybridization analysis showed that KLK4 mRNA transcripts are localized to adenocarcinoma cells of ovarian tumor tissues. Similarly, immunohistochemical staining of ovarian carcinoma sections showed immunoreactivity to KLK4 protein product (hK4) antipeptide antibodies. In addition, intracellular hK4 levels, as detected on Western blot analysis, were induced by 100 nM estrogen treatment of the estrogen receptor positive ovarian carcinoma cell line OVCAR-3, >8-24 h. Our results show that the level of KLK4 expression and expression of KLK4 mRNA variants are associated with progression of ovarian cancer, particularly late stage SER adenocarcinomas. Moreover, hK4 may be a candidate marker for the diagnosis and/or monitoring of ovarian epithelial carcinomas.
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PMID:Human kallikrein 4 (KLK4) is highly expressed in serous ovarian carcinomas. 1148 14

Our findings concerning changes in steroid receptor activation, cell kinetics and tumor growth during progression of human endometrial adenocarcinomas heterotransplanted into nude mice were reviewed. We found several major changes during the course of progression of these tumors. Such alterations as changes in estrogen receptor function, post-receptor changes and intratumor endocrine interactions were identified. Our results suggest moreover, that development of these alterations is probably genetically determined though some of the changes may be modified by the level of circulating estradiol concentrations. Through influenced tumor progression, the level of circulating estradiol may also affect hormone treatment of human endometrial adenocarcinomas.
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PMID:Changes in steroid receptor activation, cell kinetics and tumor growth rate, during progression of human endometrial adenocarcinomas growing in nude mice: a brief review. 1157 45

Selective estrogen receptor modulators (SERMs) are anti-estrogens that selectively antagonize the proliferative effects of estrogens on breast cells, thereby inhibiting or reversing neoplastic progression to clinical breast cancer. The goal is to administer these agents to healthy women with an elevated risk for breast cancer. The study reported here assessed the knowledge and attitude of 26 broadly selected women with an elevated risk for breast cancer who participated in three focus groups (eight to ten per group) that discussed the use of SERMs, such as tamoxifen and raloxifen. Data were analyzed by cross-case procedure using variable-oriented strategies. Acceptance of breast cancer chemoprevention treatment with SERMs was found to be influenced by various factors, including a knowledge of breast cancer risk factors, the perception of personal risk for breast cancer, and the perception of barriers and benefits to receiving chemoprevention treatment. The issues involved in making the decision to accept treatment with SERMs are discussed. Most of the participants in the groups indicated they were unlikely to accept breast cancer chemoprevention treatment with SERMs.
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PMID:Chemoprevention of breast cancer with selective estrogen receptor modulators: views from broadly diverse focus groups of women with elevated risk for breast cancer. 1174 64

The fragile histidine triad (Fhit) gene, which is frequently lost in many cancers, was identified as a candidate tumor suppressor gene at chromosome 3p locus 14.2. Loss of Fhit expression is an important step in tumor progression from premalignancy, to in situ, to invasive breast carcinoma. To determine whether the absence of Fhit protein correlates with other established pathological-clinical parameters or prognosis, we assessed Fhit expression using immunohistochemistry in 166 invasive breast carcinomas. Lost or significantly decreased Fhit protein expression was identified in 70 cases (42.2%). Fhit expression was inversely correlated with histological grade (P < 0.0001), negative estrogen receptor status (P = 0.0016), p53 overexpression (P = 0.0040), and tumor proliferation activity (P = 0.0006). Survival curves determined by the Kaplan-Meier method and univariate analysis demonstrated that reduced expression of Fhit was associated with a poor outcome (P = 0.0086, by log-rank test). Multivariate analysis using the stepwise Cox proportional hazard model showed that lymph node metastasis was related to poor survival rates; in addition, patients with loss of Fhit expression still tended to have poor survival (P = 0.0563). Therefore, loss of Fhit expression is associated with higher malignant phenotypes and appears to be a prognostic factor in breast carcinoma.
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PMID:Clinicopathological significance of fragile histidine triad transcription protein expression in breast carcinoma. 1175 77


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