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

Chemotherapeutic drug resistance is a major clinical problem and cause for failure in the therapy of human cancer. One of the goals of molecular oncology is to identify the underlying mechanisms, with the hope that more effective therapies can be developed. Several mechanisms have been suggested to contribute to chemoresistance: 1) amplification or overexpression of the P-glycoprotein family of membrane transporters (eg, MDR1, MRP, LRP) which decrease the intracellular accumulation of chemotherapy; 2) changes in cellular proteins involved in detoxification (eg, glutathione S-transferase pi, metallothioneins, human MutT homologue, bleomycin hydrolase, dihydrofolate reductase) or activation of the chemotherapeutic drugs (DT-diaphorase, nicotinamide adenine dinucleotide phosphate:cytochrome P-450 reductase); 3) changes in molecules involved in DNA repair (eg, O6-methylguanine-DNA methyltransferase, DNA topoisomerase II, hMLH1, p21WAF1/CIP1; 4) activation of oncogenes such as Her-2/neu, bcl-2, bcl-XL, c-myc, ras, c-jun, c-fos, MDM2, p210 BCR-abl, or mutant p53. An overview of these resistance mechanisms is presented, with a particular focus on the role of oncogenes. Some current strategies attempting to reverse their effects are discussed.
 ...
PMID:Role of oncogenes in resistance and killing by cancer therapeutic agents. 909 Apr 98

We previously reported that overexpression of the HER2/NEU oncogene induces all-TRANS retinoic acid (ATRA) resistance in breast cancer cells. N-(4-hydroxyphenyl)-retinamide (4HPR), a synthetic analogue of ATRA, has been shown to repress the expression of HER2/neu and its family member, epidermal growth factor receptor (EGFR). We investigated whether 4HPR, by suppressing HER2/neu or EGFR expression, could sensitize breast cancer cells to ATRA. At 1.3 micro M concentration (a clinically pharmacologically achievable dose), 4HPR increased ATRA sensitivity synergistically in HER2/NEU-overexpressing BT-474, MDA-MB-453, and MCF-7/Her2 breast cancer cells. However, 4HPR did not sensitize EGFR-overexpressing MDA-MB-468, Hs578T, and MCF-7/EGFR breast cancer cells to ATRA. The increased inhibitory effects in HER2/NEU-overexpressing cells were not correlated with increases in expression levels of p21(WAF1/CIP1) or retinoblastoma protein. Combining 4HPR with ATRA may lead to a novel, selective therapeutic or chemopreventive strategy against HER2/NEU-overexpressing breast tumors.
 ...
PMID:N-(4-hydroxyphenyl)-retinamide selectively increases All-TRANS retinoic acid inhibitory effects in HER2/NEU-overexpressing breast cancer cells. 1259 44

Elevated levels of p21WAF1/CIP1, an important mediator of DNA repair, have been observed in various aggressive tumors as well as linked to chemoresistance. We examined whether heregulin (HRG), a member of the EGF-like growth factor family closely related to breast cancer tumorigenesis and metastasis, modulates p21WAF1/CIP1 expression and cellular localization. We used a model system that consisted of MCF-7 cells and MCF-7 cells engineered to overexpress the full-length cDNA of the human HRG gene (MCF-7/HRG). MCF-7/HRG cells demonstrate constitutive hyperactivation of Her-2/neu receptor as well as activation of down-stream PI-3'K/AKT and MAPK signaling cascades. Immunoblotting analyses showed that MCF-7/HRG cells significantly up-regulate p21WAF1/CIP1 expression relative to control MCF-7/pBABE cells, while a strong nuclear accumulation of p21WAF1/CIP1 in MCF-7/HRG cells was revealed by immunofluorescence microscopy studies. Protein degradation analyses demonstrated that the half-life of p21WAF1/CIP1 protein was increased from approximately 35 min in control MCF-7/pBABE cells to >/=3 h in MCF-7/HRG cells. Pharmacological inactivation of the PI-3'K/AKT and MAPK completely prevented HRG-induced accumulation of p21WAF1/CIP1. A structural deletion mutant of HRG (HRG-M4) lacking the N-terminus sequence and the cytoplasmic-transmembrane region of HRG was generated to investigate whether secretion of HRG and transactivation of Her-2/neu actively contributed to HRG-regulated p21WAF1/CIP1 expression and cellular localization. MCF-7 cells engineered to overexpress HRG-M4 did not demonstrate either activation of Her-2/neu, PI-3'K/AKT, or MAPK. Remarkably, HRG-M4 overexpression completely abolished the ability of HRG to promote nuclear accumulation of p21WAF1/CIP1 and concomitantly enhanced the apoptotic effects of cisplatin towards breast cancer cells. This novel interplay between HRG and p21WAF1/CIP1 strongly suggests that one mechanism of HRG-regulated breast cancer cell proliferation, survival, and/or sensitivity to genotoxic damage is to stabilize and promote a nuclear accumulation of p21WAF1/CIP1.
 ...
PMID:Heregulin-triggered Her-2/neu signaling enhances nuclear accumulation of p21WAF1/CIP1 and protects breast cancer cells from cisplatin-induced genotoxic damage. 1570 20

There is an urgent need to identify and develop a new generation of therapeutic agents and systemic therapies targeting the estradiol (E2)/estrogen receptor (ER) signaling in breast cancer. In this regard, new information on the mechanisms of E2/ER function and/or cross talk with other prosurvival cascades should provide the basis for the development of other ideal anti-E2 therapies with the intent to enhance clinical efficacy, reduce side effects or both. Our very recent assessment of the mechanisms by which cancer-associated increased lipogenesis and its inhibition alters the E2/ER signaling discovered that fatty acid synthase (FASN), the enzyme catalyzing the terminal steps in the de novo biosynthesis of long-chain fatty acids, differentially modulates the state of sensitivity of breast and endometrial cancer cells to E2-stimulated ER transcriptional activation and E2-dependent cell growth and survival: 1) pharmacological inhibition of FASN activity induced a dramatic augmentation of E2-stimulated ER-driven gene transcription, whereas interference (RNAi)-mediated silencing of FAS gene expression drastically lowered E2 requirements for optimal activation of ER transcriptional activation in breast cancer cells; conversely, pharmacological and RNAi-induced inhibition of FASN worked as an antagonist of E2- and tamoxifen-dependent ER transcriptional activity in endometrial adenocarcinoma cells; 2) pharmacological and RNAi-induced inhibition of FASN synergistically enhanced E2-mediated down-regulation of ER protein and mRNA expression in breast cancer cells, whereas specific FASN blockade resulted in a marked down-regulation of E2-stimulated ER expression in endometrial cancer cells; and 3) FASN inhibition decreased cell proliferation and cell viability by promoting apoptosis in hormone-dependent breast and endometrial cancer cells. In this review we propose that, through a complex mechanism involving the regulation of MAPK/ER cross talk as well as critical E2-related proteins including the Her-2/neu (erbB-2) oncogene and the cyclin-dependent kinase inhibitors p21(WAF1/CIP1) and p27(Kip1), a previously unrevealed connection exists between FASN and the genomic and nongenomic ER activities in breast and endometrial cancer cells. From a clinical perspective, we suggest that if chemically stable FASN inhibitors or cell-selective systems able to deliver RNAi targeting FASN gene demonstrate systemic anticancer effects of FASN inhibition in vivo, additional preclinical studies to characterize their anti-breast cancer actions should be of great interest as the specific blockade of FASN activity may also provide a protective means against endometrial carcinoma associated with tamoxifen-based breast cancer therapy.
 ...
PMID:Targeting fatty acid synthase in breast and endometrial cancer: An alternative to selective estrogen receptor modulators? 1680 39