Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04626 (erbB-2)
 5,251 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

For several decades, clinical and histologic assessment of various phenotypic properties has provided a basis for treatment planning. However, it is recognized that, preoperatively, clinical assessment identifies only 20% of patients with advanced disease. Furthermore, the variability in intraoperative sampling, the subjectivity and limitations of histologic interpretation, and the variability in response to standardized treatment modalities represent concerns associated with the current treatment of endometrial carcinoma. Presumably, early dissemination, early recurrence, treatment refractoriness and, ultimately, compromised survival are reflections of the inherent biologic characteristics of the tumor. A reasonable assumption is that proscribed molecular events determine various behavioral characteristics of tumors that become manifested at the time of transformation rather than evolving as the tumor volume increases. Therefore, the identification of one or more of these quantifiable molecular variables that directly or indirectly assess tumor biology would assist clinicians in determining patient risk status and in selecting treatment options. As noted, DNA ploidy is an independent, broadly applicable, quantifiable predictor of progression-free survival in patients with endometrial cancer and, therefore, warrants designation as a major prognostic factor or therapeutic determinant. Aneuploidy implies the presence of an abnormal quantity of genomic material and imparts a progressively less favorable prognosis as the DNA index increases. These assayable aberrancies of cellular DNA content presumably reflect the more extreme alterations at the molecular level. Because neoplastic transformation is generally a multistep process, aberrations in several proto-oncogenes or tumor suppressor genes (or both) presumably must be realized before a clinical malignancy develops. A number of genes that encode for various regulatory proteins are overexpressed in endometrial cancer. Whether these aberrancies are fundamental to the pathogenesis of this disease process is unclear. Nevertheless, there appears to be an association between DNA ploidy and the overexpression of several regulatory genes, such as c-fms, K-ras, HER-2/neu, and p53. Although overexpression of these oncogenes and tumor suppressor genes harbor prognostic significance in endometrial cancer, the ploidy status of the tumor appears to represent the most cogent objective variable. As the etiopathogenesis of endometrial carcinoma becomes more discernible, one can envision a limited number of tissue-specific molecular-genetic indices characterizing the risk status of patients. Because the estimated number of deaths from endometrial cancer has doubled since 1987, reassessing of the therapeutic determinants for this disease process is important. The management objective for endometrial cancer by the turn of the century should be the identification of patients at high risk for advanced disease or post-treatment recurrences (or both) at the time of clinical declaration of symptoms and diagnosis. Such pretreatment identification would afford patients at high risk for advanced or recurrent disease access to physicians with special expertise and would facilitate the evaluation and application of new or modified therapeutic modalities. Equally important would be the identification of patients at low risk for untoward outcome, thereby avoiding the cost and morbidity of excessive therapeutic measures.
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PMID:Endometrial neoplasia: prognostic significance of ploidy status. 886 93

The Rotating-Wall Vessel (RWV) is a novel in vitro cell culture system used to successfully culture a cell line derived from a heterologous mixed mullerian tumor cell of the ovary. Although the original tumor was comprised of both epithelial and mesodermal components, long-term culture in conventional flasks established a cell line from this tumor with homogeneous epitheliallike growth characteristics (1). Cells from Passage 36 were seeded into a Rotating-Wall Vessel containing Cytodex-3 microcarrier beads. Scanning electron micrographs of tumor cells cultured for 32 d in the RWV showed the presence of heterogeneous cell populations organized into three-dimensional tissuelike architecture. Immunocytochemical analysis confirmed the cellular heterogeneity, as demonstrated by expression of both epithelial and mesenchymal antigens. Reverse transcription polymerase chain reaction amplification demonstrated the presence of mRNA for cellular oncogenes HER-2/neu, H-ras, K-ras, and tumor suppressor p53. Thus, there are two advantages to propagation of tissue in the RWV culture system:(a) tissue diversification representing populations present in the original tumor, and (b) the three-dimensional freedom to organize tissues morphologically akin to those observed in vivo. These data indicate that the RWV culture system is suitable for generating large quantities of ovarian tumor cells in vitro that are amenable to immunocytochemical, oncogenic, morphologic characteristics demonstrated in vivo.
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PMID:Three-dimensional culture of a mixed mullerian tumor of the ovary: expression of in vivo characteristics. 919 95

Epidemiologic studies have shown that the risk of cancer in the ovarian surface epithelium is decreased by factors that suppress ovulation, whereas uninterrupted ovulation has been associated with increased risk. This suggests that ovulation may play a critical role in ovarian carcinogenesis. More recently, molecular studies have demonstrated alterations in specific oncogenes and tumor suppressor genes in ovarian cancers. Overexpression of the HER-2/neu oncogene occurs in approximately 30% of ovarian cancers and correlates with poor survival. Although mutation of the K-ras oncogene has been found in some mucinous ovarian cancers, mutations in this gene appear to be more common in borderline ovarian tumors. Amplification of c-myc occurs in approximately 30% of ovarian cancers and is more frequently seen in serous cancers. Mutation of the p53 tumor suppressor gene, with resultant overexpression of mutant p53 protein, occurs in 50% of stage III/IV and 15% of stage I/II ovarian cancers. Most p53 mutations in ovarian cancers are transitions, which suggests that they arise spontaneously rather than due to exogenous carcinogens. In contrast to the acquired genetic alterations described above that are a feature of sporadic ovarian cancers, 5-10% of ovarian cancers probably arise due to inherited genetic defects. Recently, the BRCA1 tumor suppressor gene has heen identified and shown to be responsible for most cases of hereditary ovarian cancer. Further studies are needed to augment our understanding of the molecular pathogenesis of ovarian cancer.
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PMID:Human ovarian cancer of the surface epithelium. 933 69

Pancreatic cancer is the fifth leading cause of cancer death in the United States, and despite improvements in the results of surgical treatment for this disease, little impact has been made upon overall mortality. New advances in treatment will depend upon improved adjuvant therapy, early diagnosis, and a better understanding of tumor biology. This article summarizes the results of molecular genetic studies in pancreatic cancer and their potential clinical significance. Familial predisposition to pancreatic cancer, cytogenic studies, DNA ploidy analysis, and examination of specific oncogenes and tumor suppressor genes are reviewed. The most frequent mutations detected have been in the K-ras oncogene, which occur in 80% of pancreatic cancers. These mutations do not correlate with tumor stage or survival, but can be useful in differentiating pancreatic exocrine from endocrine tumors and chronic pancreatitis. Mutations in the p53 gene occur in approximately 50% of tumors, and appear to be an independent prognostic factor for patient survival. Mutations in the CDKN2 gene are frequently seen in sporadic pancreatic cancers, and have been implicated in cases of familial pancreatic cancer. The significance of mutations in APC, MCC, DCC, c-erbB-2, RB-1, and mismatch repair genes in the genesis of pancreatic cancer is less clear.
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PMID:The molecular genetics of pancreatic cancer. 936 57

Human pancreatic cancers overexpress a number of important tyrosine growth factor receptors and their ligands. These include the epidermal growth factor (EGF) receptor (EGFR) and related receptors, multiple ligands that bind to EGFR, certain fibroblast growth factors (FGF) receptors (FGFR) and ligands, and insulin-like growth factor I (IGF-I) and its receptor. The excessive activation of mitogenic signaling cascades that are modulated by these overexpressed ligands and receptors is compounded by the presence of mutations in the K-ras oncogene. Pancreatic cancers also overexpress transforming growth factor betas (TGF-betas) that usually inhibit the growth of epithelial cells. Pancreatic cancers, however, underexpress the type I TGF-beta receptor and harbor mutations in the smad4 gene, alterations that prevent TGF-betas from inhibiting cancer cell growth but that do not confer onto pancreatic actions that promote cancer growth in vivo. Together, these perturbations confer onto pancreatic cancer cells a tremendous growth advantage.
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PMID:Role of growth factors in pancreatic cancer. 944 85

Patients with non-small-cell lung cancer (NSCLC) survive for variable lengths of time, even when adjustment is made for pathological stage. Numerous reports suggest that biological markers predict survival in patients undergoing surgery for NSCLC with curative intent, but many of these claims are unconfirmed or conflicting. We postulated that the use of multiple putative markers might provide greater power in predicting survival. We studied 101 consecutive patients with NSCLC who underwent exploratory thoracotomy and who were followed for at least 2 yr. We assessed mutations in the p53 tumor suppressor gene (exons 5-8) and the K-ras oncogene (codons 12 and 13) by polymerase chain reaction amplification and single strand conformation polymorphism of the product. We identified 19 K-ras mutations (all adenocarcinomas except for two) and 40 p53 mutations among the 101 cases. We also evaluated p53 protein, bcl-2 protein, c-erbB-1 protein, c-erbB-2 protein, and MIA-15-5 antigen by standard immunocytochemical techniques, and we found that all of these antigens were variably expressed. As expected, we found a strong inverse association between surgical tumor stage and survival. Of the molecular markers studied, only MIA-15-5 antigen expression correlated strongly with survival by univariate analysis (p = 0.001) and it remained a significant predictor by multivariate analysis (p = 0.01). However, in this study, overexpression of MIA-15-5 antigen predicted an improved survival, whereas the original report showed a worse prognosis (N. Engl. J. Med. 1992;327:14). We conclude the multiple cell markers are not clinically useful in predicting survival among patients undergoing surgery for NSCLC. Differences between our results and prior reports may be due to chance, to true population differences, or to other factors.
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PMID:Do molecular markers predict survival in non-small-cell lung cancer? 956 24

The EGF-like family of proteins, such as epidermal growth factor (EGF), transforming growth factor alpha (TGFalpha), amphiregulin (AR), betacellulin (BTC), cripto-1 (CR-1), and heregulin (HRG), plays an important role in the pathogenesis of several human carcinomas as autocrine growth factors. Differentiation and proliferation of rat thyroid cells in culture (FRTL-5 cells) are regulated by thyrotropin (TSH); withdrawal of TSH from culture medium produces growth arrest, whereas its addition to quiescent cells stimulates cell entry into S phase. Instead, transformed thyroid cell lines as FRTL-5H2 cell line, overexpressing erbB-2, Kimol cells, transformed by the wild-type K-ras and A6 clone, transformed by a temperature sensitive K-ras mutant, can grow without addition of TSH to the culture medium. In order to identify whether EGF-like growth factors and corresponding receptors (erbB-2, erbB-3, and erbB-4) could be involved in the autonomous growth of these transformed rat thyroid epithelial cells, Northern blot for mRNA analysis and Western blot for protein expression were performed. In contrast to normal control FRTL-5 cells, both K-ras and erbB-2-transformed cells expressed elevated levels of erbB-2 receptor. Moreover, both K-ras transformed cells, Kimol and A6 cells, but no FRTL-5H2 cells, were found able to express also high levels of erbB-4 receptor and HRG/NDF ligand. Treatment of K-ras transformed thyroid cells with neutralizing antibody against HRG/NDF reduced by 50% cell proliferation. These data indicate that unlike the erbB-2 overexpressing FRTL-5 cells, in K-ras rat thyroid epithelial cells, the growth factor heregulin signals through the heterodimer erbB-2/erbB-4 receptors in an autocrine fashion.
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PMID:Heregulin-dependent autocrine loop regulates growth of K-ras but not erbB-2 transformed rat thyroid epithelial cells. 964 26

A new human cancer cell line was established from a metastatic lesion of a small cell lung carcinoma (SCLC-R1) and maintained in continuous culture with a doubling time of 62 h. The SCLC-R1 line, whose ultrastructural features are presented, showed a diploid DNA content, a translocation involving chromosome 16 [t(16;?)(q24;?)] and noticeable deletions in the FHIT (fragile histidine triad) region in the short arm of chromosome 3 [del(3)(p14)] and in the telomeric region of the short arm of chromosome 12 [del(12)(p13)]. The involvement of 12p in metastatic small cell lung cancer is reported here for the first time. No amplification or rearrangements were evident in the c-myc, L-myc, N-myc, int-2, c-erbB-2, H-ras, K-ras, c-mos, and hst-1 genes by Southern blot analysis. Wild-type p53, RB, K-ras and H-ras genes were evident by polymerase chain reaction-single-strand conformation polymorphism (PCR-SSCP) analysis. The neuron specific enolase (NSE) level was much higher in the cell line's cytosol than in the patient's serum and the cell line also had high expression of chromogranin A and cytokeratin 19. SCLC-R1 cells were sensitive to cisplatin, carboplatin and doxorubicin. The clinical history of the patient from whom the cell line was derived is reported. The characteristics of this new cell line indicate it to be a useful experimental model to investigate lung cancer biology and anticancer drug response.
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PMID:Chromosomal alterations, biological features and in vitro chemosensitivity of SCLC-R1, a new cell line from human metastatic small cell lung carcinoma. 971 81

The remnant stomach after partial gastrectomy is considered to have a predilection for the development of primary gastric carcinoma. However, early gastric stump carcinomas are uncommon because the diagnosis of gastric stump carcinoma is more difficult than that of carcinoma in the intact stomach. Triple early gastric stump carcinomas, as in the present case, are exceedingly rare and may provide some clues for further investigation of carcinogenesis in the gastric stump. We studied about the histological appearance, genetic alterations (P-53 gene, c-erbB-2 gene and K-ras gene), and expression of tumor-associated antigens (carcinoembryonic antigen, carbohydrate antigen 19-9, and sialyl-Tn) in this rare case. The three carcinomas differed from each other histologically. With respect to genetic alterations, c-erbB-2 was amplified in one lesion, but no mutations of K-ras and P-53 gene were detected. The three carcinomas also differed from each other on the expression of tumor-associated antigens. In noncancerous mucosal epithelium at the anastomosis showing hyperplasia and cystic formation of glandular epithelial cells, no genetic alterations were detected, but sialyl-Tn and carbohydrate antigen 19-9 were expressed. These results suggest that there may be different processes of carcinogenesis of the three carcinomas even though they occurred under identical environmental conditions to those that have increased cancer risk.
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PMID:Multiple early gastric stump carcinomas after gastrectomy for peptic ulcer. 973 51

Adenocarcinoma of the pancreas carries a grave prognosis for affected patients. Certain oncogenes (K-ras and HER-2/neu) are mutated in a large proportion of these aggressive tumors. Adenocarcinoma of the pancreas has also been associated with loss of tumor suppressor genes (p53, DPC4, p16/MTS), either by deletion or by mutation and loss of function. Growth factors (EGF, TGF-alpha, HGF) and growth factor receptors (EGF-R, c-met, CCK) are expressed at levels not found in the normal pancreas. Finally, factors important for angiogenesis (FGF, integrins, selectins) are likely to play an important role in the growth and metastasis of clinically relevant tumors. This review attempts to summarize and assimilate current research into the molecular and cellular biology of pancreatic cancer.
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PMID:The molecular and cellular biology of pancreatic cancer. 980 1


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