Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:O76050 (neu)
 3,969 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A principal difference between malignant and normal cells is the aberrant expression of oncogenes. Previously, we have reported on the expression of the insulin-like growth factor 1 receptor (IGF-1-R) in 93% of the human primary breast cancers studied. In the present study, we observed an increased gene copy number of the IGF-1-R in only 19 (2%) of 975 cases studied. The gene copy number of tumors with an amplified IGF-1-R gene varies between 3 and 56 (median, 24 copies). In 11 breast tumor samples with high (greater than or equal to 20 copies) IGF-1-R gene copy numbers, an additional amplification of either the c-myc gene (n = 3) or int-2/bcl-1 genes (n = 5) was observed, whereas no amplification of the HER2/neu gene was detected. The c-fes gene (like the IGF-1-R gene located on chromosome 15q25-qter), was found coamplified with the IGF-1-R in two cases, in one case to the same high extent (38 gene copies, each) and in the other case to only a moderate extent (4 copies of the c-fes gene and 21 copies of the IGF-1-R gene). Tumors with an amplified IGF-1-R gene showed a noticeable increased expression of the IGF-1-R as measured by ligand binding assays on membrane preparations. The median amount of the IGF-1-R protein of the amplified tumors was observed to be 35 times higher when compared to nonamplified tumors (P less than 0.001). Patients with tumors containing a high (greater than or equal to 20 copies) IGF-1-R gene copy number tend to have a shorter median overall survival (42 months; range, 14-120+; n = 8) than patients with tumors having a low amplified (3-10 copies) IGF-1-R gene copy number (median, 77 months; range, 19.5-98+; n = 4).
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PMID:Sporadic amplification of the insulin-like growth factor 1 receptor gene in human breast tumors. 131 Jun 36

Breast cancer is one of the common cancers and is a leading cause of cancer mortality in women. The TG.NK transgenic mouse line on FVB strain background expresses the c-neu oncogene under the control of a MMTV promoter in mammary tissue and appears to be a useful animal model for evaluation of strategies to delay or prevent mammary cancer. Fiber-rich nonpurified diet (NTP-2000) and some retinoid analogues have delayed mammary cancer in the TG.NK model. Four week old hemizygous TG.NK female mice with MMTV/c-neu (erbB2) activated oncogene were fed NTP-2000 diet containing the retinoid analogue 4-hydroxyphenylretinamide (4-HPR) at 7 mmol/kg or the arotinoid Ro 40-8757 at 1.5 and 2.5 mmol/kg for 26 weeks. The 4-HPR at 7 mmol/kg diet delayed the development of palpable tumors up to 24 weeks, but by 26 weeks, the incidence markedly increased and was closer to the NTP-2000 diet control group. However, the 4-HPR diet markedly decreased the average weight of the tumors at 26 weeks with no decrease in multiplicity. The 4-HPR also caused significant increase in liver weights without an effect on body weight. Arotinoid Ro 40-8757 caused marked decrease in the number and branching of mammary ducts, and inhibited mammary tumor development with significant decrease in the incidence, multiplicity, and tumor weights compared to the NTP-2000 diet control. Arotinoid also caused a significant dose-related increase in liver weights without a significant effect on body weights. At the doses tested, the arotinoid but not 4-HPR decreased the circulating levels of IGF-1. However, there was no association between the IGF-1 levels and the size, incidence, or absence of tumors when evaluated for any treatment group or for all mice in the study irrespective of treatment. The oncogene erbB2 (c-neu) and the growth factor EGF expression were more prominent in the small tumors of the mice treated with arotinoid than in the larger tumors of the control group. PCNA staining was observed in areas where there was high erbB2 and EGF staining. The delay in onset of mammary tumors by the above retinoid analogues may be related to the delay in development of mammary glands.
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PMID:Changes associated with delay of mammary cancer by retinoid analogues in transgenic mice bearing c-neu oncogene. 1071 86

Nordihydroguaiaretic acid (NDGA) is a phenolic compound isolated from the creosote bush Larrea divaricatta that has anti-cancer activities both in vitro and in vivo. We can now attribute certain of these anti-cancer properties in breast cancer cells to the ability of NDGA to directly inhibit the function of two receptor tyrosine kinases (RTKs), the insulin-like growth factor receptor (IGF-1R) and the c-erbB2/HER2/neu (HER2/neu) receptor. In MCF-7 human breast cancer cells, low micromolar concentrations of NDGA inhibited activation of the IGF-1R, and downstream phosphorylation of both the Akt/PKB serine kinase and the pro-apoptotic protein BAD. In mouse MCNeuA cells, NDGA also inhibited ligand independent phosphorylation of HER2/neu. To study whether this inhibitory effect in cells was due to a direct action on these receptors, we studied the IGF-1-stimulated tyrosine kinase activity of isolated IGF-1R, which was inhibited by NDGA at 10 muM or less. NDGA was also effective at inhibiting autophosphorylation of the isolated HER2/neu receptor at similar concentrations. In addition, NDGA inhibited IGF-1 specific growth of cultured breast cancer cells with an IC50 of approximately 30 muM. NDGA treatment (intraperitoneal injection 3 times per week) also decreased the activity of the IGF-1R and the HER2/neu receptor in MCNeuA cells implanted into mice. This inhibition of RTK activity was associated with decreased growth rates of MCNeuA cells in vivo. These studies indicate that the anti-breast cancer properties of NDGA are related to the inhibition of two important RTKs. Agents of this class may therefore provide new insights into potential therapies for this disease.
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PMID:Nordihydroguaiaretic acid (NDGA) inhibits the IGF-1 and c-erbB2/HER2/neu receptors and suppresses growth in breast cancer cells. 1631 81

Tea is one of the most popular beverages consumed worldwide. Epidemiologic studies show an inverse relationship between consumption of tea, especially green tea, and development of cancers. Numerous in vivo and in vitro studies indicate strong chemopreventive effects for green tea and its constituents against cancers of various organs. (-)-Epigallocatechin-3-gallate (EGCG), the major catechin in green tea, appears to be the most biologically active constituent in tea with respect to inhibiting cell proliferation and inducing apoptosis in cancer cells. Recent studies indicate that the receptor tyrosine kinases (RTKs) are one of the critical targets of EGCG to inhibit cancer cell growth. EGCG inhibits the activation of EGFR (erbB1), HER2 (neu/erbB2) and also HER3 (neu/erbB3), which belong to subclass I of the RTK superfamily, in various types of human cancer cells. The activation of IGF-1 and VEGF receptors, the other members of RTK family, is also inhibited by EGCG. In addition, EGCG alters membrane lipid organization and thus inhibits the dimerization and activation of EGFR. Therefore, EGCG inhibits the Ras/MAPK and PI3K/Akt signaling pathways, which are RTK-related cell signaling pathways, as well as the activation of AP-1 and NF-kappaB, thereby modulating the expression of target genes which are associated with induction of apoptosis and cell cycle arrest in cancer cells. These findings are significant because abnormalities in the expression and function of RTKs and their downstream effectors play a critical role in the development of several types of human malignancies. In this paper we review evidence indicating that EGCG exerts anticancer effects, at least in part, through inhibition of activation of the specific RTKs and conclude that targeting RTKs and related signaling pathway by tea catechins might be a promising strategy for the prevention of human cancers.
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PMID:Targeting receptor tyrosine kinases for chemoprevention by green tea catechin, EGCG. 1932 45