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 aim of this study was to evaluate the potential of dynamic magnetic resonance imaging (MRI) enhanced by macromolecular contrast agents to monitor noninvasively the therapeutic effect of an anti-angiogenesis VEGF receptor kinase inhibitor in an experimental cancer model. MDA-MB-435, a poorly differentiated human breast cancer cell line, was implanted into the mammary fat pad in 20 female homozygous athymic rats. Animals were assigned randomly to a control (n=10) or drug treatment group (n=10). Baseline dynamic MRI was performed on sequential days using albumin-(GdDTPA)30 (6.0 nm diameter) and ultrasmall superparamagnetic iron oxide (USPIO) particles (approximately 30 nm diameter). Subjects were treated either with PTK787/ZK 222584, a VEGF receptor tyrosine kinase inhibitor, or saline given orally twice daily for 1 week followed by repeat MRI examinations serially using each contrast agent. Employing a unidirectional kinetic model comprising the plasma and interstitial water compartments, tumor microvessel characteristics including fractional plasma volume and transendothelial permeability (K(PS)) were estimated for each contrast medium. Tumor growth and the microvascular density, a histologic surrogate of angiogenesis, were also measured. Control tumors significantly increased (P<0.05) in size and in microvascular permeability (K(PS)) based on MRI assays using both macromolecular contrast media. In contrast, tumor growth was significantly reduced (P<0.05) in rats treated with PTK787/ZK 222584 and K(PS) values declined slightly. Estimated values for the fractional plasma volume did not differ significantly between treatment groups or contrast agents. Microvascular density counts correlated fairly with the tumor growth rate (r=0.64) and were statistically significant higher (P<0.05) in the control than in the drug-treated group. MRI measurements of tumor microvascular response, particularly transendothelial permeability (K(PS)), using either of two macromolecular contrast media, were able to detect effects of treatment with a VEGF receptor tyrosine kinase inhibitor on tumor vascular permeability. In a clinical setting such quantitative MRI measurements could be used to monitor tumor anti-angiogenesis therapy.
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PMID:MRI monitoring of tumor response following angiogenesis inhibition in an experimental human breast cancer model. 1272 42

The influence of transforming growth factor beta (TGF-beta) signaling on Neu-induced mammary tumorigenesis and metastasis was examined with transgenic mouse models. We generated mice expressing an activated TGF-beta type I receptor or dominant negative TGF-beta type II receptor under control of the mouse mammary tumor virus promoter. When crossed with mice expressing activated forms of the Neu receptor tyrosine kinase that selectively couple to the Grb2 or Shc signaling pathways the activated type I receptor increased the latency of mammary tumor formation but also enhanced the frequency of extravascular lung metastasis. Conversely, expression of the dominant negative type II receptor decreased the latency of Neu-induced mammary tumor formation while significantly reducing the incidence of extravascular lung metastases. These observations argue that TGF-beta can promote the formation of lung metastases while impairing Neu-induced tumor growth and suggest that extravasation of breast cancer cells from pulmonary vessels is a point of action of TGF-beta in the metastatic process.
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PMID:Transforming growth factor beta signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. 1286 Oct 75

The EphA2 receptor tyrosine kinase is found at low levels on nontransformed adult breast epithelial cells but is frequently overexpressed on aggressive breast cancer cells. Recent studies have documented an inverse relationship between EphA2 and estrogen receptor expression in breast cancer cell lines. In our present study, we demonstrate that overexpression of EphA2 decreases estrogen dependence as defined using both in vitro and in vivo criteria. The EphA2-transfected cells demonstrate increased growth in vitro and form larger and more aggressive tumors in vivo. EphA2 overexpression also decreases the ability of tamoxifen to inhibit breast cancer cell growth and tumorigenesis. These effects of EphA2 overexpression can be overcome by antibody-based targeting of EphA2. In particular, certain EphA2 antibodies can resensitize EphA2-overexpressing breast tumor cells to tamoxifen. These results have important implications for understanding the molecular basis underlying estrogen dependence and provide further evidence that EphA2 may provide a much-needed therapeutic target for breast cancer.
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PMID:EphA2 overexpression decreases estrogen dependence and tamoxifen sensitivity. 1281 Jun 80

Activated Ras utilises several downstream pathways, including the mitogen-activated protein kinase (MAPK) kinase (MEK)/MAPK pathway and the phosphoinositide 3-kinase (PI-3k)/Akt pathway, to promote cell proliferation and to inhibit apoptosis. To investigate which pathway plays a major role in Ras-induced drug resistance to chemotherapeutic agents in breast cancer cells, we transfected MCF7 breast cancer cells with a constitutively active H-RasG12V and examined the toxicities of three commonly used breast cancer chemotherapeutic agents, paclitaxel, doxorubicin, and 5-fluorouracil in these cells under the conditions that PI-3K or MEK were selectively inhibited by their respective specific inhibitors or dominant negative expression vectors. We found that Ras-mediated drug resistance is well correlated with resistance to apoptosis induced by anticancer agents in MCF7 breast cancer cells. Although inhibition of MEK/MAPK or PI-3K/Akt can each enhance the cytotoxicity of paclitaxel, doxorubicin, or 5-fluorouracil, inhibition of the PI-3K/Akt pathway seems to have a greater effect than inhibition of the MEK/MAPK pathway in reversing Ras-mediated drug resistance. Our results indicate that the PI-3K pathway may play a more important role in receptor tyrosine kinase-mediated resistance to chemotherapy and suggest that PI-3K/Akt might be a critical target molecule for anticancer intervention in breast cancer.
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PMID:Roles of the PI-3K and MEK pathways in Ras-mediated chemoresistance in breast cancer cells. 1283 22

EGFr/HER1 and c-erbB-2/HER2 expression are associated with poor prognosis in breast cancer. The type I receptor tyrosine kinase (RTK) family to which they belong has four members (HER1-4). In this study, expression of HER1-4 and oestrogen receptor (ER) expression were determined by immunohistochemistry in 220 breast carcinomas. Elevated expression of HER1 was observed in 16.4%, HER2 in 22.8%, HER3 in 17.5%, and HER4 in 11.9% of these tumours. Patients whose tumours overexpressed HER1, 2 or 3 had reduced survival (p= <0.001), whereas those whose tumours overexpressed HER4 had increased survival (p=0.013); 38.6% of cases overexpressed one or more of HER1, 2 or 3. HER4 was rarely overexpressed with other HERs (1.4% of cases). Cox's multiple regression analysis demonstrated that overexpression of HER1/2/3, HER4, and standard prognostic indicators independently affected survival. HER1-3 expression was related to ER negativity (p<0.0001, chi2). Patients with ER-positive, HER1-3-positive tumours had a significantly poorer survival (p<0.001) than those with ER-positive/HER-negative or HER4-positive tumours. Expression of HER RTKs displays complex interactions between different family members. There is a strong interaction, in terms of survival, between HER expression and ER expression. The development of HER-targeted agents (eg Herceptin, Iressa), and agents targeted at the downstream signalling pathways, therefore provides new possibilities in the treatment of breast cancer.
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PMID:Expression of the HER1-4 family of receptor tyrosine kinases in breast cancer. 1284 22

ErbB2 is a receptor tyrosine kinase whose activity in normal cells depends on dimerization with another ligand-binding ErbB receptor. In contrast, amplification of c-erbB2 in tumors results in dramatic overexpression and constitutive activation of the receptor. Breast cancer cells overexpressing ErbB2 depend on its activity for proliferation, because treatment of these cells with ErbB2-specific antagonistic antibodies or kinase inhibitors blocks tumor cells in the G1 phase of the cell cycle. Intriguingly, loss of ErbB2 signaling is accompanied by a decrease in the phosphotyrosine content of ErbB3. On the basis of these results, it has been proposed that ErbB3 might be a partner for ErbB2 in promoting cellular transformation. To test this hypothesis and directly examine the role of the "kinase dead" ErbB3, we specifically ablated its expression with a designer transcription factor (E3). By infection of ErbB2-overexpressing breast cancer cells with a retrovirus expressing E3, we show that ErbB3 is an essential partner in the transformation process. Loss of functional ErbB2 or ErbB3 has similar effects on cell proliferation and cell cycle regulators. Furthermore, expression of constitutively active protein kinase B rescues the proliferative block induced as a consequence of loss of ErbB2 or ErbB3 signaling. These results demonstrate that ErbB2 overexpression and activity alone are insufficient to promote breast tumor cell division. Furthermore, we identify ErbB3's role, which is to couple active ErbB2 to the phosphatidylinositol 3-kinase/protein kinase B pathway. Thus, the ErbB2/ErbB3 dimer functions as an oncogenic unit to drive breast tumor cell proliferation.
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PMID:The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. 1285 64

The development of the mammary gland requires the coordinated expression of hormones and growth factors. Likewise, some transformed breast cells continue to respond to these same extracellular signals. Thus, understanding the mechanisms that control normal development of tissues can lead to new therapeutic targets. The insulin-like growth factor (IGF) system plays an important role in the normal development and function of the mammary gland. Accumulating evidence suggests that the IGFs are also key regulators of the malignant phenotype. The IGFs stimulate proliferation, promote survival, and enhance metastatic potential of breast cancer cells. Although multiple receptors for the IGFs have been identified, the IGFs primarily exert their biologic effects through ligation of the type I IGF receptor tyrosine kinase (IGF1R). IGF binding to the IGF1R initiates an intracellular signaling cascade that leads to changes in gene expression and cell biology. This review will focus on the evidence that the IGF1R is a relevant treatment target in breast cancer.
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PMID:The type-1 insulin-like growth factor receptor tyrosine kinase and breast cancer: biology and therapeutic relevance. 1288 9

A crosstalk between cellular estrogen response and receptor tyrosine kinase signaling has been shown in a variety of estrogen receptor (ER)-positive cell lines. We intended to examine the presence of estrogenic growth factor effects in an ER alpha-negative breast cancer cell line. By means of reporter gene assays, we investigated the activation of estrogen response elements (EREs) by epidermal growth factor (EGF) in the estrogen-unresponsive cell line MDA-MB-231. Our results demonstrate the H-ras-dependent activation of EREs after EGF treatment in this estrogen-unresponsive cell line, an effect which was not observed in the ERalpha/beta-positive breast cancer cell line MCF-7. In MDA-MB-231 cells, the transcriptional activity of an ERE-containing promotor was enhanced dose dependently by all tested EGF concentrations. This effect could be blocked by co-treatment with the epidermal growth factor receptor (EGFR) inhibitors AG1478 and ZD1839, as well as by co-transfection with a vector coding for a dominant negative H-ras mutant, but not by co-treatment with the pure antiestrogen ICI182,780. Furthermore, expression of constitutively active H-ras was shown to be sufficient to activate EREs in MDA-MB-231 cells. Our results suggest alternative utilization of ERE-mediated gene regulation in an estradiol-unresponsive breast cancer cell line in response to an EGF stimulus. This mechanism was shown to be dependent on EGFR and H-ras activity, but independent of the presence of functional ERalpha.
Breast Cancer Res Treat 2003 Jul
PMID:H-ras dependent estrogenic effects of epidermal growth factor in the estrogen-independent breast cancer cell line MDA-MB-231. 1290 18

Transformation of breast cells occurs through loss or mutation of tumor suppressor genes, or activation or amplification of oncogenes, leading to deregulation of signal transduction pathways, abnormal amplification of growth signals, and aberrant expression of genes that ultimately transform the cells into invasive cancer. The goal of cancer preventive therapy, or "chemoprevention," is to eliminate premalignant cells or to block the progression of normal cells into cancer. Multiple alterations in signal pathways and transcription factors are observed in mammary gland tumorigenesis. In particular, estrogen receptor (ER) deregulation plays a critical role in breast cancer development and progress, and targeting ER with selective ER modulators (SERMs) has achieved significant reduction of breast cancer incidence in women at high risk for breast cancer. However, not all breast cancer is prevented by SERMs, because 30-40% of the tumors are ER-negative. Other receptors for retinoids, vitamin D analogs and peroxisome proliferator-activiator, along with transcription factors such as AP-1, NF-kappaB, and STATs (signal transducers and activators of transcription) affect breast tumorigenesis. This is also true for the signal transduction pathways, for example cyclooxygenase 2 (Cox-2), HER2/neu, mitogen-activated protein kinase (MAPK), and PI3K/Akt. Therefore, proteins in pathways that are altered during the process of mammary tumorigenesis may be promising targets of future chemopreventive drugs. Many newly-developed synthetic or natural compounds/agents are now under testing in preclinical studies and clinical trials. Receptor selective retinoids, receptor tyrosine kinase inhibitors (TKIs), SERMs, Cox-2 inhibitors, and others are some of the promising novel agents for the prevention of breast cancer. The chemopreventive activity of these agents and other novel signal transduction inhibitors are discussed in this chapter.
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PMID:Novel agents for the prevention of breast cancer: targeting transcription factors and signal transduction pathways. 1458 63

Epidermal growth factor (EGF) receptor (EGFR) is commonly amplified and/or mutated in high-grade gliomas. Abnormal signaling from this receptor tyrosine kinase is believed to contribute to the malignant phenotypes seen in these tumors. Highly specific small molecule inhibitors of this receptor tyrosine kinase have been developed and may potentially improve the treatment of these highly aggressive brain tumors. A glioma cell line overexpressing EGFR was developed to mimic the situation of a malignant glioma with amplified EGFR, and this line was used to characterize the response to specific EGFR inhibitors. Treatment of our in vitro glioma model with the EGFR kinase inhibitors ZD1839 (Iressa) or PD153035, synthetic anilinoquinazolines with high specificity for EGFR, resulted in significant suppression of EGFR autophosphorylation even with very low levels of drug. However, significantly higher levels of drug were required to fully inhibit signaling through the phosphatidylinositol 3'-kinase/AKT and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (ERK) pathways. Interestingly, not all downstream signaling pathways displayed this resistance to inhibition. EGF-dependent activation of signal transducers and activators of transcription-3 occurred at low doses of EGFR inhibitors. The uncoupling of EGFR autophosphorylation and signaling through AKT and ERK was not dependent on EGFR overexpression. In addition, although this response was seen in other glioma and the SK-BR3 breast cancer cell lines, it was not universally present. The SQ20B head and neck squamous carcinoma cell line demonstrated loss of EGF-dependent AKT and ERK activation even at low doses of inhibitor. Despite significant loss of EGF-dependent autophosphorylation, the inability of low levels of EGFR inhibitor to suppress some downstream signaling pathways in our model glioma cell line permitted continued EGF-responsive decreases in the expression of the cyclin-dependent kinase inhibitor p27KIP and EGF-dependent proliferation/cell cycle progression. Although the mechanism responsible for the differential sensitivity of the various signal transduction pathways to EGFR inhibitors remains unclear, signaling through erbB2 does not appear to be involved. The ability of certain tumor cells to maintain signaling through AKT and ERK under EGFR inhibition may represent a potential mechanism of resistance by which a tumor cell may escape the antiproliferative activity of this new class of drugs.
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PMID:Resistance to small molecule inhibitors of epidermal growth factor receptor in malignant gliomas. 1461 44


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