Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HER-2, a protooncogene located on chromosome 17q21, encodes a transmembrane glycoprotein (p185) with tyrosine kinase activity. Alterations of the HER-2 gene have been implicated in the carcinogenesis and prognosis of breast cancer and other solid tumors. It is also a cancer-therapeutic target for antibody-based therapy against the HER-2 protein. A single-nucleotide polymorphism (SNP) at codon 655, resulting in a G-to-A transition (Ile655Val) in the transmembrane domain-coding region of this gene has been associated with an increased risk of breast cancer, particularly among younger women. To understand the importance of this finding throughout the world, we evaluated this polymorphism in Ghanaian, Kenyan, Sudanese, Caucasian, African-American, Saudi, and Filipino subjects using a polymerase chain reaction-restriction fragment length polymorphism assay. The frequency of the Val allele, which is associated with increased breast cancer risk, was highly variable between populations (0%-24%). Continental African populations had a lower frequency of the Val allele than did Saudi, Chinese, Filipino, Caucasian, and African-American subjects. The data suggest that this SNP has variable frequency in different ethnic groups. The findings in this study correspond with the lower incidence and lower risk of breast cancer in African women compared with Caucasian and African-American women.
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PMID:Ethnic variation in the HER-2 codon 655 genetic polymorphism previously associated with breast cancer. 1216 52

Bile acids have been implicated in biliary tract carcinogenesis, in part, by activating the epidermal growth factor receptor (EGFR). Overexpression of Mcl-1, a potent antiapoptotic protein of the Bcl-2 family, has also been reported in cholangiocarcinomas. Because receptor tyrosine kinases like EGFR may modulate antiapoptotic protein expression, we examined the hypothesis that bile acids modulate Mcl-1 expression levels via EGFR. Deoxycholate increased cellular Mcl-1 protein in a concentration-dependent manner. The deoxycholate-mediated increase of cellular Mcl-1 protein was blocked equally by EGFR tyrosine kinase inhibitors or an EGFR-neutralizing antibody. Although inhibition of mitogen-activated protein kinases did not attenuate the deoxycholate-associated increase in Mcl-1 protein, the Raf-1 inhibitor, BAY 37-9751, effectively blocked the cellular increase of this protein. Neither Mcl-1 transcriptional activity nor its mRNA stability was altered by deoxycholate treatment. However, Mcl-1 protein stability was increased by bile acid treatment, an effect duplicated by proteasome inhibition. Deoxycholate prolongation of Mcl-1 turnover was blocked by either EGFR inhibitors or the Raf-1 inhibitor. Whereas the deoxycholate-induced increase in Mcl-1 reduced Fas-mediated apoptosis, the Raf-1 inhibitor potentiated Fas apoptosis. Our results demonstrate that bile acids block Mcl-1 protein degradation via activation of an EGFR/Raf-1 cascade resulting in its cellular accumulation. Raf-1 inhibitors block this increase of Mcl-1 and render the cells more susceptible to apoptosis, a potential therapeutic strategy for cholangiocarcinomas.
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PMID:Bile acids inhibit Mcl-1 protein turnover via an epidermal growth factor receptor/Raf-1-dependent mechanism. 1243 43

The thyroid TRK oncogenes are generated by chromosomal rearrangements juxtaposing the neurotrophic tyrosine receptor kinase type 1 (NTRK1) tyrosine kinase domain to foreign activating sequences. TRK oncoproteins display a constitutive tyrosine kinase activity resulting in the capability to transform NIH3T3 cells. The TRK oncoproteins' signal transduction has been in part elucidated, and it involves several signal transducers activated by the NGF-stimulated NTRK1 receptor. In this paper, we investigate the role of FRS2 and FRS3, two related adapter proteins activated by fibroblast growth factor and NTRK1 receptors, in the signaling of the thyroid TRK-T1 and TRK-T3 oncogenes. By a combination of in vitro and in vivo assays, we demonstrate that both fibroblast growth factor receptor substrate (FRS)2 and FRS3 are recruited and activated by TRK-T1 and TRK-T3. Interaction studies using different TRK-T3 mutants indicate that FRS3 is recruited by the same tyrosine residue interacting with Shc and FRS2. Expression studies show different expression patterns of the FRS adapters in normal and tumor thyroid samples: FRS3 is expressed in both normal and thyroid tumor samples, whereas FRS2 is not expressed in normal thyroid but is differentially expressed in some tumors. Altogether, our data indicate that the FRS2 and FRS3 adapters may have a role in thyroid carcinogenesis triggered by TRK oncogenes.
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PMID:The signaling adapters fibroblast growth factor receptor substrate 2 and 3 are activated by the thyroid TRK oncoproteins. 1258 69

In the human epidermis, the cells most at risk for the development of cancer due to sunlight exposure are the keratinocytes. In animal models, ultraviolet-B is a complete carcinogen, capable of inducing and promoting the development of malignant cells. A key element of ultraviolet-B-induced carcinogenesis is the ability of ultraviolet-B to induce the expression of a number of cellular proteins and activate growth factor receptor tyrosine kinases, including the erbB receptor family. Keratinocytes express the erbB1 (also called EGF-R, HER1), the erbB2 (also known as neu or HER2), and the erbB3 (HER3) subtypes. In general, activation of the erbB receptor family leads to a cellular proliferative response. In certain instances, however, activation of an erbB receptor can induce differentiation, cell cycle arrest, and even apoptosis. The inhibition of tyrosine kinase activity in rodent models and human skin has been shown to inhibit some ultraviolet-B response pathways. We have shown that the inhibition of erbB receptors, by both pharmaceutical and immunologic means, will inhibit ultraviolet-B-induced apoptosis in the HaCaT human keratinocyte cell line. This inhibition was specific for the erbB receptor family and specific for ultraviolet-B-induced apoptosis. These results suggest that, in certain instances, ultraviolet-B-induced apoptotic signaling requires erbB family receptor activity.
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PMID:Inhibition of erbB receptor family members protects HaCaT keratinocytes from ultraviolet-B-induced apoptosis. 1260 63

Thyroid cancers are a leading cause of death due to endocrine malignancies. RET/PTC (rearranged in transformation/papillary thyroid carcinomas) gene rearrangements are the most frequent genetic alterations identified in papillary thyroid carcinoma. Although the oncogenic potential of RET/PTC is related to intrinsic tyrosine kinase activity, the substrates for this enzyme are yet to be identified. In this report, we show that phosphoinositide-dependent kinase 1 (PDK1), a pivotal serine/threonine kinase in growth factor-signaling pathways, is a target of RET/PTC. RET/PTC and PDK1 colocalize in the cytoplasm. RET/PTC phosphorylates a specific tyrosine (Y9) residue located in the N-terminal region of PDK1. Y9 phosphorylation of PDK1 by RET/PTC requires an intact catalytic kinase domain. The short (iso 9) and long forms (iso 51) of the RET/PTC kinases (RET/PTC1 and RET/PTC3) induce Y9 phosphorylation of PDK1. Moreover, Y9 phosphorylation of PDK1 by RET/PTC does not require phosphatidylinositol 3-kinase or Src activity. RET/PTC-induced phosphorylation of the Y9 residue results in increased PDK1 activity, decrease of cellular p53 levels, and repression of p53-dependent transactivation. In conclusion, RET/PTC-induced tyrosine phosphorylation of PDK1 may be one of the mechanisms by which it acts as an oncogenic tyrosine kinase in thyroid carcinogenesis.
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PMID:RET/PTC (rearranged in transformation/papillary thyroid carcinomas) tyrosine kinase phosphorylates and activates phosphoinositide-dependent kinase 1 (PDK1): an alternative phosphatidylinositol 3-kinase-independent pathway to activate PDK1. 1273 63

The interaction of osteopontin (OPN) with CD44 and alphavbeta3-integrin has been implicated in numerous signal transduction pathways that may promote cancer metastasis. CD44v6 is a splice variant of CD44 which has been identified as a marker of cancer progression. In this study, immortalized liver carcinoma cells (HepG2) were used to examine the effect of OPN on two isoforms of CD44: CD44 standard (CD44 s) and CD44v6. Western blots demonstrated that OPN up-regulated plasma membrane CD44v6 protein expression in a concentration- and time-dependent fashion. CD44v6 levels returned to control levels when OPN-alphavbeta3-integrin binding was blocked by an RGD peptide or tyrosine kinase activity was inhibited. OPN significantly increased CD44v6 protein synthesis, while simultaneously decreasing protein degradation. Steady-state mRNA levels of both CD44s and CD44v6 were unaltered in the presence of OPN stimulation. OPN increased HepG2 in vitro adhesion to hyaluronate (HA); excess soluble HA extinguished OPN-mediated HepG2 adhesion, indicating CD44 dependence. In conclusion, OPN binds to the alphavbeta3-integrin to increase plasma membrane CD44v6 expression and augment in vitro adhesion to HA. This may contribute to the mechanism by which OPN enhances metastatic behavior in hepatocellular cancer cells.
Carcinogenesis 2003 Dec
PMID:Osteopontin-dependent CD44v6 expression and cell adhesion in HepG2 cells. 1294 55

Characterization of intracellular signaling pathways should lead to a better understanding of ovarian epithelial carcinogenesis and provide an opportunity to interfere with signal transduction targets involved in ovarian tumor cell growth, survival, and progression. Challenges toward such an effort are significant because many of these signals are part of cascades within an intricate and likely redundant intracellular signaling network (Fig.1). For instance, a given signal may activate a dual intracellular pathway (ie, MEK1-MAPK and PI3K/Akt required for fibronectin-dependent activation of matrix metalloproteinase 9). A single pathway also may transduce more than one biologic or oncogenic signal (ie, PI3K signaling in epithelial and endothelial cell growth and sprouting of neovessels). Despite these challenges, evidence for therapeutic targeting of signal transduction pathways is accumulating in human cancer. For instance, the EGF-specific tyrosine kinase inhibitor ZD 1839 (Iressa) may have a beneficial therapeutic effect on ovarian epithelial cancer. Therapy of this cancer may include inhibitors of PI kinase (quercetin), ezrin and PIP kinase (genistein). The G protein-coupled family of receptors, including LPA, also is an attractive target to drugs, although their frequent pleiotropic functions may be at times toxic and lack specificity. Because of the lack of notable toxicity, PI3K/Akt pathway inhibitors such as FTIs are a promising targeted therapy of ovarian epithelial cancer. Increasing insight into the oncogenic pathways involved in ovarian epithelial cancer also is helping clinicians to understand better the phenomenon of chemoresistance in this malignancy. Oncogenic activation of gamma-synuclein promotes cell survival and provides resistance to paclitaxel, but such a resistance is partially overcome by an MEK inhibitor that suppresses ERK activity. Ovarian epithelial cancer is a complex group of neoplasms with an overall poor prognosis. Comprehension of this cancer pathobiology suffers because of an incomplete understanding of precursor lesions and the absence of an orthotopic animal model until very recently. It can be predicted with confidence, however, that the discovery of potent inhibitors of signal transduction and the development of discovery tools, such as proteomics and metabolomics, may change the way by which clinicians may now address basic biomedical questions in this insidious and lethal disease.
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PMID:Oncogenic pathways implicated in ovarian epithelial cancer. 1295 83

Head and neck squamous cell carcinomas (HNSCC) are characterized by upregulation of the epidermal growth factor receptor (EGFR), where EGFR serves as a potential therapeutic target. We previously reported that a gastrin-releasing peptide/gastrin-releasing peptide receptor (GRP/GRPR) autocrine growth pathway is activated early in HNSCC carcinogenesis. In the present study, we examined the mechanism of EGFR activation by GRP/GRPR in HNSCC proliferation. In HNSCC cells that express elevated levels of both GRPR and EGFR, we found that GRP induced rapid phosphorylation of EGFR as well as p44/42-MAPK activation. Using several EGFR-specific tyrosine kinase inhibitors and cells derived from EGFR knockout mice, we demonstrated that GRP-induced p44/42-MAPK activation was dependent upon EGFR activation. Further investigation demonstrated that cleavage of transforming growth factor-alpha (TGF-alpha) by matrix metalloproteinases mediated GRP-induced MAPK activation. In addition, HNSCC proliferation stimulated by GRP was eliminated upon specific inhibition of EGFR or MEK, and GRP failed to stimulate proliferation in EGFR-deficient cells. These results imply that the mitogenic effects of GRP in HNSCC are mediated by extracellular release of TGF-alpha and require the activation of an EGFR-dependent MEK/MAPK-dependent pathway.
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PMID:Mitogenic effects of gastrin-releasing peptide in head and neck squamous cancer cells are mediated by activation of the epidermal growth factor receptor. 1367 57

Cholangiocarcinoma (CCA) is a lethal disease, afflicting many thousands the world over. Human CCA develops through a multi-step progression model, preceded by the onset of dysplasia in the cholangiolar ductal epithelium. An animal model of multi-step carcinogenesis in the biliary tree will enable the study of genetic changes in human CCA, and provide an avenue for chemoprevention strategies. We describe an oral thioacetamide (TAA)-induced model of rat CCA that recapitulates the histologic progression of human CCA. Male Sprague-Dawley (SD) rats (n = 170), weighing 350 +/- 20 g, were used in this study. Drinking water with TAA 300 mg/l was administered orally, and the liver was harvested and examined histologically at weekly intervals, beginning at 5 weeks after initiation of TAA. Harvested tissues were formalin-fixed and paraffin embedded for morphologic and immunohistochemical studies. Multifocal bile ductular proliferation with intestinal metaplasia (presence of goblet cells) and increasing histologic atypia (biliary dysplasia) was observed by the 9th week of TAA administration. Biliary cytokeratin (CK19)-expressing invasive intestinal-type CCA with stromal desmoplasia was evident at the 16th week, and by the 22nd week, the yield rate for CCAs had increased to 100%. Invasive CCAs preceded the development of hepatic cirrhosis by at least 4 weeks; the earliest incidence of hepatic fibrosis was observed beginning at 20 weeks post-TAA administration. The progression from normal cholangioles to biliary dysplasia to invasive CCA was accompanied by up-regulation of the proto-oncogenes c-met and c-erbB-2, tyrosine kinase receptors over-expressed in human CCAs. The study was terminated at 6 months, at which time no systemic metastases or deaths were observed. Oral administration of TAA in drinking water to male SD rats provides a reproducible animal model for development of CCA with a high yield rate. In particular, the presence of biliary dysplasia beginning at the 9th week, which progresses to invasive CCA, mimics the multi-step model of human CCA. The TAA rat model may serve as a powerful pre-clinical platform for therapeutic and chemoprevention strategies for human CCA.
Carcinogenesis 2004 Apr
PMID:Thioacetamide-induced intestinal-type cholangiocarcinoma in rat: an animal model recapitulating the multi-stage progression of human cholangiocarcinoma. 1465 42

The epidermal growth factor receptor (EGFR) is expressed in a wide variety of solid tumours. It has been demonstrated that the EGFR-associated signaling pathway plays an important role in carcinogenesis and cancer progression. In the new therapeutic paradigm of molecular-targeted cancer therapy, interference with intracellular signaling cascades is an appealing treatment approach. Inhibitory strategies under study include monoclonal antibodies, tyrosine kinase inhibitors, EGFR-ligand conjugates, EGFR immunoconjugates, and antisense oligonucleotides. Many of these strategies have demonstrated efficacy against EGFR-expressing tumour cells in preclinical studies, prompting a large number of clinical trials. In particular, clinical studies using monoclonal antibody blockade and EGFR tyrosine kinase inhibitors have suggested that EGFR blockade is a well-tolerated and effective treatment strategy; however, more trials are needed to precisely define how these agents will fit into modern cancer care.
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PMID:Epidermal growth factor receptor: a promising target in solid tumours. 1476 23


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