UMLS:C0006142 - FACTA Search

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Query: UMLS:C0006142 (breast cancer)
160,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Abnormalities in G1/S transition in cell cultures have been attributed to alterations in ErbB (erythroblastic leukaemia viral [v-erb-b] oncogene homologue, avian) signalling, cyclin D1 overexpression or disturbance of the p21(WAF1) (p21)-mediated cell cycle arrest induced by p53. To investigate the significance of these mechanisms on an early stage of human breast tumour growth, we studied the expression of EGFR (ErbB1), HER-2/neu (ErbB2), cyclin D1, p21 and p53 as well as oestrogen (ER) and progesterone receptor (PgR) in paraffin sections of 45 ductal carcinoma in situ (DCIS) by immunohistochemistry. Cell proliferation was assessed by immunohistochemical quantification of Ki-67. Five cases with cyclin D1 overexpression were analysed by FISH for CCND1 amplification. Increased proliferative activity was observed in 46% of DCIS. It was correlated with the expression of EGFR and HER-2/neu (p < 0.05), but neither with cyclin D1 and p21 overexpression nor with p53 accumulation. ErbB positive status was associated with p21 overexpression (p < 0.05). In addition we found a correlation between the overexpression of p21 and cyclin D1 restricted to ErbB-positive cases (p = 0.013). ErbB-negative tumours with increased proliferative activity were ER and cyclin D1 positive. No CCND1 amplification was detected in the analysed cases. In conclusion, our data support that EGFR and HER-2/neu play an important role in cell cycle control in DCIS. p21 appears to be a potential mediator of ErbB signalling. We propose that cyclin D1 could be indirectly induced by ErbB signalling through p21. Besides, ER-mediated upregulation of cyclin D1 seems to be a possible mechanism of maintaining cell proliferation in DCIS in case of EGFR- and HER-2/neu-negativity.
Breast Cancer Res Treat 2003 May
PMID:EGFR, HER-2/neu, cyclin D1, p21 and p53 in correlation to cell proliferation and steroid hormone receptor status in ductal carcinoma in situ of the breast. 1282 53

In earlier studies, we and others have established that activation of EGFR can promote survival in association with upregulation of Bcl-x(L). However, the mechanism responsible for upregulation of Bcl-x(L) is unknown. For the current studies we have chosen pro-apoptotic, c-Myc-overexpressing murine mammary epithelial cells (MMECs) derived from MMTV-c-Myc transgenic mouse tumors. We now demonstrate that EGFR activation promotes survival through Akt and Erk1/2. Blockade of EGFR kinase activity and the PI3-K/Akt and MEK/Erk pathways with pharmacological inhibitors resulted in a significant induction of cellular apoptosis, paralleled by a downregulation of both Akt and Erk1/2 proteins. Consistent with a survival-promoting role of Akt, we observed that constitutively activated Akt (Myr-Akt) inhibited apoptosis of pro-apoptotic, c-Myc-overexpressing cells following the inhibition of EGFR tyrosine kinase activity. In addressing possible downstream effectors of EGFR through activated Akt, we detected significant upregulation of Bcl-x(L) protein, suggesting this pro-survival protein is a target of Akt in MMECs. By using pharmacological inhibitors of PI3-K/Akt and MEK/Erk together with dominant-negative Akt and Erk1 we observed the decrease in Bcl-x(L) protein. Our findings may be of importance for understanding the emerging role of Bcl-x(L) as a potential marker of poor prognosis in breast cancer.
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PMID:Epidermal growth factor inhibition of c-Myc-mediated apoptosis through Akt and Erk involves Bcl-xL upregulation in mammary epithelial cells. 1283 94

The Erb-B family of receptors plays an important role in lung carcinogenesis and tumor development, and EGFR and HER2 are highly expressed in bronchial preneoplasia. In invasive tumors, EGFR are expressed in 50-90%, and mostly in squamous cell carcinomas, but also in adenocarcinomas and large cell carcinomas, while HER2 is less frequently expressed (20-30%) and mostly expressed in adenocarcinomas. Bronchioloalveolar cell carcinomas may present a distinct EGFR profile compared to the other NSCLCs and evidence and consequences are discussed. The genetic mechanisms responsible for overexpression of EGFR and HER2 proteins might be numerous, including gene dosage (overrepresentation or amplification) as well as translational and post-translational mechanisms. However, for EGFR and HER2 there is a positive correlation between gene copy numbers and level of protein expression demonstrated by fluorescence in situ hybridization analysis and immunochemistry. Gene amplification for EGFR and HER2 is demonstrated in only 5-10% of the tumors. The treatment status and therapeutic limitation with trastuzumab (Herceptin) in lung cancer compared to breast cancer is discussed.
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PMID:Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. 1286 60

Previous work has shown that phorbol esters modulate chemotaxis. Here, we demonstrate that PKC activation via phorbol 12-myristate 13-acetate (PMA) treatment of MDA-MB-231 cells inhibits EGF-induced cell spreading, the initial event of motility and chemotaxis. Of five PKC isoforms (alpha,iota,lambda,delta,and epsilon) identified in this cell line, PMA treatment only induced PKCalpha translocation from the cytosol to the membrane, an event that correlated with the development of the rounded morphology. Cell recovery was linked to PKCalpha downregulation in part via the proteasome pathway since treatment with MG101 in the presence of PMA did not lead to PKCalpha degradation and cell recovery. Co-immunoprecipitation and immunolocalization demonstrated that EGF co-localized with PKCalpha and EGFR, however, PMA did not abrogate EGFR transactivation. This work suggests that PKCalpha is the primary target of PMA acting as a transient negative regulator of cell spreading and motility in MDA-MB-231 breast cancer cells.
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PMID:Protein kinase Calpha negatively regulates cell spreading and motility in MDA-MB-231 human breast cancer cells downstream of epidermal growth factor receptor. 1287 87

PP1R1B-ERBB2-GRB7 locus on human chromo-some 17q12 is frequently amplified in gastric and breast cancer. Because recombination hot spot or fragile site is located around the terminus of amplified region (amplicon), we searched for a novel gene closely linked to the teromeric end of the ERBB2 amplicon. Here, we identified and characterized the ZPBP-like (ZPBPL) gene by using bioinformatics. ZPBPL gene, corresponding to BC043152 cDNA, was found to consist of seven exons. ZPBPL (316 aa) and ZPBP (351 aa) proteins, showing 34.8% total amino-acid identity, shared the zona pellucida binding protein homologous (ZPBH) domain with conserved 15 cysteine residues. ZPBPL was a secreted-type glycoprotein with the ZPBH domain, while ZPBP was a type 2 transmembrane protein with the extracellular ZPBH domain. ZPBPL mRNA was co-expressed with ZPBP mRNA in testis, germ cell tumor, and brain medulla. ZPBPL might be implicated in the gamete interaction during fertilization just like ZPBP. The MGC9753-ERBB2-MGC14832-GRB7-ZNFN1A3-ZPBPL-PRO2521-ORMDL3-GSDM locus on human chromosome 17q12-q21 and the ZPBP-ZNFN1A1-FIGNL1-DDC-GRB10-COBL-SEC61G-EGFR-LANCL2 locus on human chromosome 7p12-p11 were next compared. Comparative genomics revealed that ZPBPL-ZNFN1A3-GRB7-ERBB2 and ZPBP-ZNFN1A1-GRB10-EGFR loci were paralogous regions within the human genome. This is the first report on identification and characterization of the ZPBPL gene.
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PMID:Identification and characterization of human ZPBP-like gene in silico. 1288 58

In this study we have investigated the influence of dietary mono- and polyunsaturated lipids on 7,12-dimethylbenz(alpha)anthracene (DMBA)-induced mammary tumorigenesis, and the modulation of expression of c-erbB1/EGFR and c-erbB2/neu as a mechanism of this influence. Two series of Sprague-Dawley rats were given a single dose of DMBA. Animals from Series 1 were fed a semi-synthetic low-fat or high-fat corn oil diet, following an initiation-promotion experimental design. Rats from Series 2 were fed low-fat or different high-fat diets (rich in corn oil or rich in olive oil) in the promotion stage of mammary carcinogenesis. High corn oil diet showed clearly a stimulatory effect on experimental breast carcinogenesis, suggesting a role of this kind of lipids on initiation and promotion of mammary tumorigenesis. Moreover, results suggested that olive oil acts as a negative modulator of the experimental breast cancer. On the other hand, two transcripts of EGFR and one neu mRNA were detected by chemiluminescent Northern blot in mammary adenocarcinomas. Analysis of data showed the tendency that high-fat corn oil diet decreases the 2.7 kb mRNA of EGFR, encoding a truncated form of the receptor with no enzimatic activity. High-fat olive oil diet increased EGFR mRNA levels, specially those from 2.7 kb, and decreased the relative abundance of neu mRNA. These data suggest that the modulating effect of dietary lipids on mammary carcinogenesis could result in changes of EGFR and neu mRNA, leading to an increase of EGFR activity by high-fat corn oil diet and a decrease of EGFR and Neu signal transduction pathway by high-fat olive oil diet.
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PMID:Modulation of EGFR and neu expression by n-6 and n-9 high-fat diets in experimental mammary adenocarcinomas. 1288 17

Both epidemiological and experimental studies indicate that ethanol is a tumor promoter and may promote metastasis of breast cancer. However, the molecular mechanisms underlying ethanol-mediated tumor promotion remain unknown. Overexpression of ErbB proteins in breast cancer patients is generally associated with poor prognosis. The ErbB proteins are a family of receptor kinases that include four closely related members: epidermal growth factor receptor (EGFR/ErbB1), ErbB2/neu, ErbB3, and ErbB4. Particularly, ErbB2 plays a pivotal role in ErbB-mediated activities. Here we demonstrated that amplification of ErbB2 expression sensitized a specific cellular response to ethanol. Human breast cancer cells or mammary epithelial cells with a high expression of ErbB2 exhibited an enhanced response to ethanol-stimulated cell invasion in vitro. Ethanol also stimulated cell proliferation; however, this stimulation was independent of ErbB2 levels. Ethanol triggered divergent intracellular signaling among cells expressing different ErbB2 levels. In the cells overexpressing ErbB2, ethanol was more effective in the activation of c-Jun NH2 terminal protein kinases (JNKs) and p38 mitogen-activated protein kinase (p38 MAPK) as well as the induction of reactive oxygen species (ROS) than the cells with normal ErbB2 expression. Blockage of either JNKs or p38 MAPK activation eliminated ethanol-mediated cell invasion. In contrast, the reduction of hydrogen peroxide concentration by catalase exposure had little effect on ethanol-induced cell invasion. These results indicated that ethanol-induced cell invasion was primarily mediated by JNKs and p38 MAPK, whereas the involvement of ROS formation might be minimal. Our study suggests that overexpression of ErbB2 may augment ethanol-elicited signaling and promote ethanol-stimulated tumor metastasis.
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PMID:Overexpression of ErbB2 enhances ethanol-stimulated intracellular signaling and invasion of human mammary epithelial and breast cancer cells in vitro. 1291 29

C-erbB-2 (HER2/neu) protein overexpression or amplification has been noted in some solid tumors a molecular target for tumor suppression. C-erbB-2 protein is localized on the membrane surface and is classified in the EGFR family. Trastuzumab is a humanized monoclonal antibody which binds to the extracellular domain of the c-erbB-2 protein in breast cancer cells. Good responders to trastuzumab may be ICH 2 + and FISH positive breast tumors, and ICH 3 + cancer. The response rate is approximately 15% with single administration of trastuzumab. Combination therapy with paclitaxel for the treatment of patients with metastatic cancer may bring more than 60% response and improve time to disease progression. Congestive heart failure associated with trastuzumab may be severe, and combination therapy which includes anthracyclines increases the incidence and severity of cardiac dysfunction. Other toxicities include infusion reaction.
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PMID:[Clinical implications of trastuzumab]. 1293 63

Epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I), and heregulin-beta1 (HRG-beta1), can modulate the expression and activity of the estrogen receptor-alpha (ER-alpha) via the phosphatidylinositol 3-kinase (PI 3-K)/Akt pathway in the ER-alpha-positive breast cancer cell line, MCF-7. Estradiol can also rapidly activate PI 3-K/Akt in these cells (nongenomic effect). The recent study examines whether Akt is involved in the ER-alpha regulation by estradiol (genomic effect). Stable transfection of parental MCF-7 cells with a dominant-negative Akt mutant, as well as the PI 3-K inhibitors wortmannin and LY 294,002, blocked the effect of estradiol on ER-alpha expression and activity by 70-80 and 55-63%, respectively. Stable transfection of MCF-7 cells with a constitutively active Akt mimicked the effect of estradiol. The changes in ER-alpha expression and activity were abrogated in response to estradiol by an arginine to cysteine mutation in the pleckstrin homology (PH) domain of Akt (R25C), suggesting the involvement of this amino acid in the interaction between Akt and ER-alpha. Experiments employing selective ErbB inhibitors demonstrate that the effect of estradiol on ER-alpha expression and activity is mediated by ErbB2 and not by EGFR. Moreover, anchorage-dependent and -independent growth assays, cell cycle and membrane ruffling analyses showed that Akt exerts estrogen-like activity on cell growth and membrane ruffling and that a selective ErbB2 inhibitor, but not anti-ErbB2 antibodies directed to the extracellular domain, can block these effects. In the presence of constitutively active Akt, tamoxifen only partially inhibits cell growth. In contrast, in cells stably transfected with either a dominant-negative Akt or with R25C-Akt, as well as in parental cells in the presence of a selective ErbB2 inhibitor, the effect of estradiol on anchorage-dependent and -independent cell growth was inhibited by 50-75 and 100%, respectively. Dominant-negative Akt inhibited membrane ruffling by 54%; however, R25C-Akt did not have any effect, suggesting that kinase activity plays an important role in this process. Scatchard analysis demonstrated a 67% reduction in estrogen-binding capacity in cells transfected with constitutively active Akt. No change in binding affinity of estradiol to the receptor was observed upon transfection with either Akt mutant. Taken together, our results suggest that estradiol treatment results in binding to membrane ER-alpha and interaction with a heterodimer containing ErbB2, leading to tyrosine phosphorylation. This results in the activation of PI 3-K and Akt. Akt, in turn, may interact with nuclear ER-alpha, altering its expression and activity.
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PMID:Effect of estradiol on estrogen receptor-alpha gene expression and activity can be modulated by the ErbB2/PI 3-K/Akt pathway. 1297 Jul 48

Over-expression of members of the ErbB-receptor family has been associated with malignant transformation. The amplification of Her-2/neu in tumor tissue is now an established prognostic factor in breast cancer. In order to initiate signal transduction, ErbB-receptor monomers need to form homo- or heterodimers. The composition of these dimers is thought to influence both quality and quantity of downstream signaling pathways, and to determine the biological response. We have investigated the protein expression pattern of the four ErbB-receptors EGFR, Her-2/neu, Her-3 and Her-4, and correlated it with their putative ligands EGF, TGF-alpha and HRG in 74 women with invasive breast cancer. Using western blot-analysis on cell membrane isolates, we detected the co-expression of all four ErbB-family members in 79.7% of cases, and of all of the three investigated ligands in 82.4%. We did not observe a correlation between EGFR and Her-2/neu or Her-4 protein expression, EGFR and Her-3 (p = 0.005), and Her-3 and Her-4 (p = 0.05) were clearly co-expressed. The strongest overall correlation, was found between Her-2/neu and Her-3 (p < 0.001) and between Her-2/neu and Her-4 (p = 0.001). This was particularly true in nodal-positive tumors (p < 0.001 and p = 0.002) whereas in nodal-negative tumors the co-expression was either less significant (Her-2/neu and Her-3; p = 0.01) or not significant (Her-2/neu and Her-4). The co-expression of EGFR/Her-3 was associated with the expression of all ligands, whereas the Her-2/neu/Her-3 was correlated with HRG (p = 0.002), thereby indicating a functional relation between specific receptor-dimer combinations and putative ligands. Taken together, we have performed the first comprehensive survey of ErbB-system expression in breast cancer, and have demonstrated the presence of a co-regulated receptor/ligand system in vivo. We have further shown that Her-2/neu is the preferred co-expression partner in nodal-positive tumors and thus the most likely dimerization candidate in malignant breast tumors.
Breast Cancer Res Treat 2003 Aug
PMID:Co-expression of ErbB-family members in human breast cancer: Her-2/neu is the preferred dimerization candidate in nodal-positive tumors. 1450 8

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