Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

The effects and mechanisms of exogenous phosphatase and tensin homolog deleted from chromosome ten (PTEN) gene on phosphatase activity-dependent apoptosis of breast cancer cell line MDA468 were investigated. PTEN gene packaged with lipofectin was transferred into breast cancer cell line MDA468 and parental MDA468 cells served as controls. RT-PCR and Western blot were done to detect the expression of target genes. The expression of phosphospecific protein kinase B (PKB/Akt) and focal adhesion kinase (FAK) protein stimulated by epidermal growth factor (EGF) was also detected. Apoptosis was determined by flow cytometry with a double-staining method using FITC-conjugated annexin V and PI. MDA468 cells transfected with PTEN gene could express PTEN mRNA and protein. PTEN decreased the phosphorylation level of AKT protein and down-regulated FAK protein expression in MDA468 stimulated by EGF. The apoptosis rate was 21.68%. PTEN induced breast cancer apoptosis phosphatase activity-dependently. The mechanism is possibly related with phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB)/AKT signaling pathway. Those results may provide new clues on the gene therapy in breast cancer.
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PMID:Exogenous PTEN gene induces apoptosis in breast carcinoma cell line MDA468. 1739 12

Here, we report the identification of a metastasis promoting factor by a forward genetic screen in mice. A retroviral cDNA library was introduced into the nonmetastatic cancer cell line 168FARN, which was then orthotopically transplanted into mouse mammary fat pads, followed by selection for cells that metastasize to the lung. The genes encoding the disulfide isomerase ERp5 and beta-catenin were found to promote breast cancer invasion and metastasis. Disulfide isomerases (thiol isomerases), which catalyze disulfide bond formation, reduction, and isomerization, have not previously been implicated in cancer cell signaling and tumor metastasis. Overexpression of ERp5 promotes both in vitro migration and invasion and in vivo metastasis of breast cancer cells. These effects were shown to involve activation of ErbB2 and phosphoinositide 3-kinase (PI3K) pathways through dimerization of ErbB2. Activation of ErbB2 and PI3K subsequently stimulates RhoA and beta-catenin, which mediate the migration and invasion of tumor cells. Inhibition of ErbB2 and PI3K reverses the phenotypes induced by ERp5. Finally, ERp5 was shown to be up-regulated in human surgical samples of invasive breast cancers. These data identify a link between disulfide isomerases and tumor development, and provide a mechanism that modulates ErbB2 and PI3K signaling in the promotion of cancer progression.
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PMID:In vivo selection for metastasis promoting genes in the mouse. 1742 Apr 53

Three-dimensional extracellular matrix culture, on substrata such as Matrigel, restores many aspects of the differentiated state to non-malignant cells from a variety of tissues. We have adapted these techniques to study EGFR (epidermal growth factor receptor) signalling and drug response in breast cancer cell lines. EGFR-dependent breast cancer cell lines undergo a striking reversion of the malignant phenotype upon treatment with inhibitors targeting the receptor, or downstream signalling intermediates such as mitogen-activated protein kinase and PI3K (phosphoinositide 3-kinase). Using this approach, we have recently reported that EGFR signalling in breast cancer can be effectively inhibited by blocking the activity of a key protease, TACE [TNFalpha (tumour necrosis factor alpha)-converting enzyme], which regulates the bioavailability of EGFR ligands. These results suggest a new way to target EGFR signalling in tumours of the breast and other epithelial tissues and underline the value of three-dimensional extracellular matrix culture models for exploring cancer-relevant signalling processes ex vivo.
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PMID:Three-dimensional extracellular matrix culture models of EGFR signalling and drug response. 1763 16

Previous studies have shown that vasoactive intestinal peptide (VIP) and its receptors (VPAC(1) and VPAC(2) receptors) are involved in promotion and growth of many human tumours including breast cancer. Here we investigated whether VIP regulates the expression of the main angiogenic factor, vascular endothelial cell growth factor (VEGF) in human oestrogen-dependent (T47D) and oestrogen-independent (MDA-MB-4687) breast cancer cells. Semiquantitative and quantitative real-time RT-PCRs were used at mRNA level whereas enzyme immunoanalysis was performed at protein level. Both cancer cell lines expressed VIP and VPAC(1) (but not VPAC(2)) receptors that were functional as shown by VIP stimulation of adenylate cyclase activity. VIP induced VEGF expression at both mRNA and protein levels following a time-dependent pattern. The responses were faster in T47D than in MDA-MB-468 cells. The observed VIP regulation of VEGF expression appears to be modulated at least by the cAMP/protein kinase A (PKA) and the phosphoinositide 3-kinase (PI3-K) signalling systems as shown by studies of adenylate cyclase stimulation and using specific kinase inhibitors such as H89 and wortmannin. These actions suggest a proangiogenic potential of VIP in breast cancer.
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PMID:Vasoactive intestinal peptide (VIP) increases vascular endothelial growth factor (VEGF) expression and secretion in human breast cancer cells. 1768 7

Accumulating evidence indicates that heregulins, EGF (epidermal growth factor)-like ligands, promote breast cancer cell proliferation and are involved in the progression of breast cancer towards an aggressive and invasive phenotype. However, there is limited information regarding the molecular mechanisms that mediate these effects. We have recently established that HRG (heregulin beta1) promotes breast cancer cell proliferation and migration via cross-talk with EGFR (EGF receptor) that involves the activation of the small GTPase Rac1. In the present paper we report that Rac1 is an essential player for mediating the induction of cyclin D1 and p21(Cip1) by HRG in breast cancer cells. Inhibition of Rac function by expressing either the Rac-GAP (GTPase-activating protein) beta2-chimaerin or the dominant-negative Rac mutant N17Rac1, or Rac1 depletion using RNAi (RNA interference), abolished the cyclin D1 and p21(Cip1) induction by HRG. Interestingly, the proliferative effect of HRG was impaired not only when the expression of Rac1 or cyclin D1 was inhibited, but also when cells were depleted of p21(Cip1) using RNAi. Inhibition of EGFR, PI3K (phosphoinositide 3-kinase; kinases required for Rac activation by HRG) or MEK [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase] also blocked the up-regulation of cyclin D1 and p21(Cip1) by HRG. In addition, we found that HRG activates NF-kappaB (nuclear factor kappaB) in a Rac1- and MEK-dependent fashion, and inhibition of NF-kappaB abrogates cyclin D1/p21(Cip1) induction and proliferation by HRG. Taken together, these findings establish a central role for Rac1 in the control of HRG-induced breast cancer cell-cycle progression and proliferation through up-regulating the expression of cyclin D1 and p21(Cip1).
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PMID:Heregulin beta1 promotes breast cancer cell proliferation through Rac/ERK-dependent induction of cyclin D1 and p21Cip1. 1794 27

The CCNG2 gene that encodes the unconventional cyclin G2 was one of the few genes up-regulated on anti-human epidermal growth factor receptor 2 (HER2) antibody-mediated inhibition of HER2 signaling. The purpose of this study was to explore how HER2 signaling modulates cyclin G2 expression and the effect of elevated cyclin G2 on breast cancer cell growth. Treatment of breast cancer cells that overexpress HER2 (BT474, SKBr3, and MDAMB453) with the anti-HER2 antibody trastuzumab or its precursor 4D5 markedly up-regulated cyclin G2 mRNA in vitro and in vivo, as shown by real-time PCR. Immunoblot and immunofluorescence analysis with specific antibodies against cyclin G2 showed that anti-HER2 antibody significantly increased cyclin G2 protein expression and translocated the protein to the nucleus. Trastuzumab was not able to induce cyclin G2 expression in cells weakly expressing HER2 (MCF7) or in cells that had developed resistance to trastuzumab. Enforced expression of HER2 in T47D and MDAMB435 breast cancer cells reduced cyclin G2 levels. Collectively, these data suggest that HER2-mediated signaling negatively regulates cyclin G2 expression. Inhibition of phosphoinositide 3-kinase (LY294002), c-jun NH(2)-terminal kinase (SP600125), and mammalian target of rapamycin (mTOR)/p70 S6 kinase (p70S6K; rapamycin) increased cyclin G2 expression. In contrast, treatment with inhibitors of p38 mitogen-activated protein kinase (SB203580), mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (U0126), or phospholipase Cgamma (U73122) did not affect cyclin G2 expression. Anti-HER2 antibody in combination with LY294002, rapamycin, or SP600125 induced greater cyclin G2 expression than either agent alone. Ectopic expression of cyclin G2 inhibited cyclin-dependent kinase 2 activity, Rb phosphorylation, cell cycle progression, and cellular proliferation without affecting p27(Kip1) expression. Thus, cyclin G2 expression is modulated by HER2 signaling through multiple pathways including phosphoinositide 3-kinase, c-jun NH(2)-terminal kinase, and mTOR signaling. The negative effects of cyclin G2 on cell cycle and cell proliferation, which occur without altering p27(Kip1) levels, may contribute to the ability of trastuzumab to inhibit breast cancer cell growth.
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PMID:Roles of human epidermal growth factor receptor 2, c-jun NH2-terminal kinase, phosphoinositide 3-kinase, and p70 S6 kinase pathways in regulation of cyclin G2 expression in human breast cancer cells. 1802 71

We have previously shown that the EphA2 receptor tyrosine kinase is overexpressed in glioblastoma multiforme (GBM) and represents a novel, attractive therapeutic target for the treatment of brain tumors. Here, we have developed an EphA2-targeted agent, ephrinA1-PE38QQR, a novel cytotoxin composed of ephrinA1, a ligand for EphA2, and PE38QQR, a mutated form of Pseudomonas aeruginosa exotoxin A. EphrinA1-PE38QQR showed potent and dose-dependent killing of GBM cells overexpressing the EphA2 receptor in cell viability and clonogenic survival assays, with an average IC(50) of approximately 10(-11) mol/L. The conjugate was also highly effective in killing breast and prostate cancer cells overexpressing EphA2. The cytotoxic effect of ephrinA1-PE38QQR was specific, as it was neutralized by an excess of EphA2 ligands. Moreover, normal human endothelial cells and breast cancer cells that do not overexpress EphA2, as well as GBM cells that have down-regulated EphA2, were not susceptible to the cytotoxin. EphrinA1-PE38QQR-mediated cytotoxicity induced caspase-dependent apoptosis, which was, however, not responsible for cell death in response to the conjugate. In addition, the conjugate elicited no changes in the activity of survival pathways such as phosphoinositide 3-kinase, measured by AKT phosphorylation. This is the first attempt to create a cytotoxic therapy using any of the ephrin ligands of either class (A or B) conjugated to a bacterial toxin. EphrinA1-PE38QQR is very potent and specific, produces cell death that is caspase independent, and forms the basis for the further development of clinically applicable EphA2-targeted cytotoxins.
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PMID:A novel, potent, and specific ephrinA1-based cytotoxin against EphA2 receptor expressing tumor cells. 1808 15

Recent progress in diagnostic tools allows many breast cancers to be detected at an early preinvasive stage. Thus, a better understanding of the molecular basis of early breast cancer progression is essential. Previously, we discovered that 14-3-3 zeta is overexpressed in >40% of advanced breast cancers, and this overexpression predicts poor patient survival. Here, we examined at what stage of breast disease 14-3-3 zeta overexpression occurs, and we found that increased expression of 14-3-3 zeta begins at atypical ductal hyperplasia, an early stage of breast disease. To determine whether 14-3-3 zeta overexpression is a decisive early event in breast cancer, we overexpressed 14-3-3 zeta in MCF10A cells and examined its effect in a three-dimensional culture model. We discovered that 14-3-3 zeta overexpression severely disrupted the acini architecture resulting in luminal filling. Proper lumen formation is a result of anoikis, apoptosis due to detachment from the basement membrane. We found that 14-3-3 zeta overexpression conferred resistance to anoikis. Additionally, 14-3-3 zeta overexpression in MCF10A cells and in mammary epithelial cells (MEC) from 14-3-3 zeta transgenic mice reduced expression of p53, which is known to mediate anoikis. Mechanistically, 14-3-3 zeta induced hyperactivation of the phosphoinositide 3-kinase/Akt pathway which led to phosphorylation and translocation of the MDM2 E3 ligase resulting in increased p53 degradation. Ectopic expression of p53 restored luminal apoptosis in 14-3-3 zeta-overexpressing MCF10A acini in three-dimensional cultures. These data suggest that 14-3-3 zeta overexpression is a critical event in early breast disease, and down-regulation of p53 is one of the mechanisms by which 14-3-3 zeta alters MEC acini structure and increases the risk of breast cancer.
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PMID:14-3-3 zeta down-regulates p53 in mammary epithelial cells and confers luminal filling. 1833 56

The PI3K (phosphoinositide 3-kinase) pathway regulates cell proliferation, survival and migration and is consequently of great interest for targeted cancer therapy. Using a panel of small-molecule PI3K isoform-selective inhibitors in a diverse set of breast cancer cell lines, we have demonstrated that the biochemical and biological responses were highly variable and dependent on the genetic alterations present. p110alpha inhibitors were generally effective in inhibiting the phosphorylation of PKB (protein kinase B)/Akt and S6, two downstream components of PI3K signalling, in most cell lines examined. In contrast, p110beta-selective inhibitors only reduced PKB/Akt phosphorylation in PTEN (phosphatase and tensin homologue deleted on chromosome 10) mutant cell lines, and was associated with a lesser decrease in S6 phosphorylation. PI3K inhibitors reduced cell viability by causing cell-cycle arrest in the G(1) phase, with multi-targeted inhibitors causing the most potent effects. Cells expressing mutant Ras were resistant to the cell-cycle effects of PI3K inhibition, which could be reversed using inhibitors of Ras signalling pathways. Taken together, our data indicate that these compounds, alone or in suitable combinations, may be useful as breast cancer therapeutics, when used in appropriate genetic contexts.
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PMID:A chemical screen in diverse breast cancer cell lines reveals genetic enhancers and suppressors of sensitivity to PI3K isoform-selective inhibition. 1849 48

Three-dimensional (3D) cell culture techniques are frequently used to model alterations in tissue architecture critically important for tumor development. Here, we report on a detailed comparison of a spheroid model of human epidermal growth factor receptor (HER2) overexpressing cancer cells with the traditional monolayer culture. In 2D culture, HER2 and HER3 form heterodimers, whereas in multicellular spheroids HER2 homodimers are formed. These homodimers localize in membrane rafts, resulting in enhanced inhibition of the proliferation of cancer cells with trastuzumab (Herceptin), a monoclonal antibody specifically targeting HER2. Within the tumor spheroids, HER2 homodimerization leads to enhanced activation of HER2 and results in a switch in signaling pathways from phosphoinositide 3-kinase (PI3K) to mitogen-activated protein kinase (MAPK). Diminished PI3K signaling is accompanied by the activation of the integrin beta4/Rac1/PAK 2 signaling cascade. We propose that the described 3D culture system may better reflect some in vivo aspects of HER signaling and can be used to further improve the understanding of the molecular mechanisms of trastuzumab action. Furthermore, the described human multicellular tumor spheroids may allow identification of new targets for the treatment of HER2-positive breast cancer patients who currently benefit suboptimally from trastuzumab treatment.
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PMID:Comparison of 3D and 2D tumor models reveals enhanced HER2 activation in 3D associated with an increased response to trastuzumab. 1897 15


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