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

Several studies have shown a role of the tyrosine kinase receptor, c-kit, and its ligand, SCF, during organogenesis, normal cell development and growth of some tumor histotypes. In breast cancer, studies using different methodologies have shown conflicting results. In the present study we analyzed c-kit and SCF in 14 normal mammary epithelia samples, in 16 in situ and in 75 invasive breast cancers. The expression of c-kit and SCF protein was analyzed by immunohistochemistry and mRNA expression was evaluated by in situ hybridization and reverse-transcriptase polymerase chain reaction (RT-PCR). The different methodologies gave somewhat different results. Using immunohistochemistry and in situ hybridization, protein and mRNA expression of c-kit and SCF were high in normal mammary gland, significantly lower in in situ and almost completely undetectable in invasive breast cancer. Conversely, using RT-PCR, mRNA expression was observed in normal tissue and in all pathologic lesions of mammary gland, probably due to the high sensitivity of the methodology or to the positivity of elements other than tumor cells expressing the receptor and/or its ligand. These results suggest that the c-kit/SCF pathway plays an important role in the maintenance of normal growth of mammary epithelium and that the process of malignant transformation is accompanied by their progressive loss. Furthermore, we demonstrated that different results are attributable to different methodologies and that morphologic approaches are the most reliable for defining the cellular source of c-kit or SCF expression.
Breast Cancer Res Treat 2004 Jan
PMID:c-kit and SCF expression in normal and tumor breast tissue. 1499 53

To define the molecular changes associated with ovarian cancer, DNA microarray analysis has been adapted to detect differentially expressed genes in human normal ovary tissue, borderline, and invasive epithelial ovarian tumors. The differential expression of genes in the tumor tissues and normal tissues was confirmed by Northern and/or semi-quantitative RT-PCR analysis. Analysis of the differential gene-expression profiles of the normal and neoplastic ovary allowed us to detect previously unidentified genes in ovarian tissues. We observed up-regulation of the following genes in ovarian cancer: catechol-O-methyltransferase (COMT), the autocrine motility factor neuroleukin (NLK), the transcription regulator high mobility group I proteins (HMGI), the tyrosine kinase receptor ErbB-3, S100-alpha protein and Acyl-CoA-binding protein (ACBP). The transcription factor, chicken ovalbumin up-stream promoter transcription factor II (COUP-TFII), was the only gene down-regulated in ovarian cancer. Comparable gene-expression profiles were previously reported in breast cancer, suggesting that similar molecular events also exist in ovarian cancer. Our microarray analysis showed that most differentially expressed genes in ovarian cancer are linked to glucose/insulin metabolism, providing a possible molecular link between the glucose/insulin signaling pathway and the neoplasms of ovarian cancer.
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PMID:Microarray analysis of differentially expressed genes associated with human ovarian cancer. 1501 Aug 21

Trastuzumab (herceptin) and pertuzumab (Omnitarg, 2C4) are recombinant humanized monoclonal antibodies that target different extracellular regions of the HER-2 tyrosine kinase receptor. We explored combination effects of these agents in the HER-2-overexpressing BT474 breast cancer cell line. Trastuzumab and 2C4 synergistically inhibited the survival of BT474 cells, in part, because of increased apoptosis. Trastuzumab increased 2C4-mediated disruption of HER-2 dimerization with the epidermal growth factor receptor and HER-3. Combination drug treatment reduced levels of total and phosphorylated HER-2 protein and blocked receptor signaling through Akt but did not affect mitogen-activated protein kinase. These results suggest that combining HER-2-targeting agents may be a more effective therapeutic strategy in breast cancer rather than treating with a single HER-2 monoclonal antibody.
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PMID:The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. 1505 83

The aim of our study was to determine whether or not the tyrosine kinase receptor, HER2 (also known as ErbB2/Her2/neu), is overexpressed in human osteosarcomas (OS). We studied 15 biopsy and 18 resection specimens at the mRNA and protein levels. HER2 status in the OS specimens was assessed by immunohistochemistry (IHC) and quantitative Real-Time Polymerase chain reaction (PCR). In moderately immunopositive cases fluorescent in situ hybridisation (FISH) analysis was used in order to identify any possible gene amplification. 27 samples were evaluable for IHC and only 1 case showed a moderately positive membrane staining. The remaining samples showed no staining or focal cytoplasmic staining (2 samples). In the moderately positive case, FISH analysis showed no HER-2 gene amplification. There was also no overexpression of HER2 mRNA suggesting this sample was a false-positive immunostain. HER2 mRNA expression was present in all samples at a similar level to that in the breast cancer cell line, MCF7, which does not overexpress HER2 and was used as a negative control. In conclusion, this study shows that HER2 mRNA or membranous HER2 protein overexpression is absent in human OS. We noted various inconsistencies in previous published studies, with regard to methodology and the interpretation of the results based on poor methodology. We therefore conclude that the positive data with regard to HER2 overexpression reported in these previous studies is not reliable. Our results suggest that the monoclonal antibody trastuzumab (Herceptin(R)), directed against the HER2-receptor, is not likely to be an effective therapeutic agent in OS.
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PMID:Overexpression of the HER-2 oncogene does not play a role in high-grade osteosarcomas. 1509 66

Neuropilin-1 (NRP1) is a coreceptor to a tyrosine kinase receptor for both the vascular endothelial growth factor (VEGF) family and semaphorin (Sema) family members. NRP1 plays versatile roles in angiogenesis, axon guidance, cell survival, migration, and invasion. NRP1 contains three distinct extracellular domains, a1a2, b1b2, and c. We report here the identification of two novel soluble human NRP1 isoforms, which we named sIIINRP1 and sIVNRP1. These soluble NRP1 isoforms were generated by alternative splicing of the NRP1 gene, a common regulatory mechanism occurring in cell surface receptor families. Both sIIINRP1 and sIVNRP1 contain a1a2 and b1b2 domains, but no c domain, and the rest of the NRP1 sequence. Additionally, sIIINRP1 is missing 48 amino acids within the C-terminus of the b2 domain. Both sIIINRP1 and sIVNRP1 are expressed in human cancerous and normal tissues. These molecules are capable of binding to VEGF165 and Sema3A. Furthermore, recombinant sIIINRP1 and sIVNRP1 proteins inhibit NRP1-mediated MDA-MB-231 breast cancer cell migration. These results indicate the multiple levels of regulation in NRP1 function and suggest that these two novel NRP1 isoforms are useful antagonists for NRP1-mediated cellular activities.
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PMID:Identification of two novel alternatively spliced Neuropilin-1 isoforms. 1520 6

Nerve growth factor (NGF) has long been known for its effects on neuronal cell survival and differentiation. This prototypical neurotrophic factor stimulates neurons through two distinct classes of membrane receptors: the TrkA tyrosine kinase receptor, and the tumor necrosis factor receptor family member p75NTR, also known as the common neurotrophin receptor. Somewhat surprisingly, there is a growing body of evidence indicating that NGF is also a major stimulator of breast cancer cell growth. Both the survival and proliferation of breast cancer cells are strongly stimulated by NGF, mediated by TrkA and p75NTR respectively, utilising signaling pathways similar to those described for neurons. In addition, although NGF is produced by breast cancer cells, it is not in normal breast epithelial cells, giving rise to an autocrine stimulation of tumor growth. Therefore, NGF receptors and signaling are thus looking increasingly promising as potential drug targets for breast cancer.
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PMID:Nerve growth factor receptors and signaling in breast cancer. 1537 32

The oncogenic activity of the overexpressed HER2 tyrosine kinase receptor requires its localization in the plasma membrane. The antitumor effect of anti-HER2 antibodies (Abs) is mainly dependent on receptor downregulation and comprises p27Kip1-mediated G1 cell cycle arrest. However, one major limitation of anti-HER2 therapy is the reversibility of tumor growth inhibition after discontinuation of treatment caused by the mitogenic signaling associated with cell surface receptor re-expression. We found that the level of p27Kip1 upregulation, inhibition of Cdk2 activity and magnitude of G1 arrest induced by the humanized Ab trastuzumab (Herceptin, HCT) on BT474 and SKBr3 HER2-overexpressing breast cancer cells correlates with the level of cell surface receptor. Thus, continuous exposure of cells to HCT for 72 hr results in downregulation of the cell surface receptor and a concurrent increase in the level of p27Kip1 protein. Discontinuation of Ab exposure after the first 8 hr results in failure to upregulate p27Kip1 and arrest of cell cycle progression. We show that the lysosomotropic amine chloroquine (CQ) augments receptor internalization in HER2-overexpressing cells either pretreated or continuously treated with HCT and leads to an increased and sustained inhibitory effect. The enhanced CQ-dependent loss of functional HER2 from the cell surface resulted in sustained inactivation of the serine/threonine kinase Akt, upregulation of p27Kip1 protein and inhibition of cyclin E/Cdk2 activity. Potentiation of the inhibitory effect of HCT by CQ was directly related to loss of HER2 from the plasma membrane since prevention of Ab-mediated receptor endocytosis by engagement of the receptor with immobilized HCT abrogated the effect of CQ.
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PMID:Enhancement of the p27Kip1-mediated antiproliferative effect of trastuzumab (Herceptin) on HER2-overexpressing tumor cells. 1538 77

Trastuzumab (Herceptin) is a therapeutic monoclonal antibody specific for the human epidermal growth factor receptor type 2 (HER2), a cell-surface tyrosine kinase receptor overexpressed by 25% to 30% of breast cancers. The drug is now regarded as one option for standard therapy in HER2-overexpressing metastatic breast cancers. It is associated with a moderate response rate as a single agent, and in combination with standard chemotherapy, can produce greater response rates and prolong the survival of women with advanced breast cancer. Its activity in metastatic breast cancer has led to active clinical trials examining its potential role in the neoadjuvant and adjuvant settings. The successful clinical development of trastuzumab provides further proof of principle that biologically targeted therapies can have a profound impact on the management of breast cancer. Here we review the clinical development of this novel agent, emphasizing the potential for therapeutic synergy when trastuzumab is combined with both standard chemotherapy and innovative molecularly targeted and biologic agents.
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PMID:Trastuzumab in breast cancer. 1547 Nov 97

The tyrosine kinase receptor Ron has been implicated in several types of cancer, including overexpression in human breast cancer. This is the first report describing the effect of Ron signaling on tumorigenesis and metastasis in a mouse model of breast cancer. Mice with a targeted deletion of the Ron tyrosine kinase signaling domain (TK-/-) were crossed to mice expressing the polyoma virus middle T antigen (pMT) under the control of the mouse mammary tumor virus promoter. Both pMT-expressing wild-type control (pMT+/- TK+/+) and pMT+/- TK-/- mice developed mammary tumors and lung metastases. However, a significant decrease in mammary tumor initiation and growth was found in the pMT+/- TK-/- mice compared with controls. An examination of mammary tumors showed that there was a significant decrease in microvessel density, significantly decreased cellular proliferation, and a significant increase in terminal deoxynucleotidyl transferase-mediated nick end labeling-positive staining in mammary tumor cells from the pMT+/- TK-/- mice compared with the pMT+/- TK+/+ mice. Biochemical analyses on mammary tumor lysates showed that whereas both the pMT-expressing TK+/+ and TK-/- tumors have increased Ron expression compared with normal mammary glands, the pMT-expressing TK-/- tumors have deficits in mitogen-activated protein kinase and AKT activation. These results indicate that Ron signaling synergizes with pMT signaling to induce mammary tumor formation, growth, and metastasis. This effect may be mediated in part through the regulation of angiogenesis and through proliferative and cell survival pathways regulated by mitogen-activated protein kinase and AKT.
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PMID:Ron receptor signaling augments mammary tumor formation and metastasis in a murine model of breast cancer. 1573 14

The HER2 gene encodes a tyrosine kinase receptor overexpressed in 25-30% of human breast cancers. Clinical trials have shown the efficacy of the anti-HER2 monoclonal antibody Trastuzumab in metastatic breast cancer patients. Nevertheless, 70% of patients are unresponsive from start of treatment and nearly all become unresponsive during treatment. Possible mechanisms for these failures could depend on impairment of the machinery responsible for receptor downregulation. To test this hypothesis, we analysed the genomic sequences encoding regions known to be critical for HER2 downregulation, of both HER2 and of the ubiquitin ligase Cbl. We investigated 63 breast cancers, and found no mutations in these regions. We thus considered alternative mechanisms -- such as TGFalpha production -- possibly interfering with HER2 downregulation. In selected cases, by comparing breast cancer neoplastic tissue before and after Trastuzumab treatment, we found induction of TGFalpha expression. Moreover, by in vitro expression of exogenous TGFalpha in breast cancer cells, we observed a dramatic reduction in Trastuzumab-induced HER2 endocytosis, downregulation and cell growth inhibition. Our results suggest that unresponsiveness to Trastuzumab may not be due to intrinsic defects in the machinery responsible for HER2 downregulation, but can be associated with a TGFalpha-related mechanism of escape to HER2 downregulation.
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PMID:TGFalpha expression impairs Trastuzumab-induced HER2 downregulation. 1573 15


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