Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278488 (metastatic breast cancer)
 7,812 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The EGF family of proteins encompasses several polypeptides such as epidermal growth factor (EGF), transforming growth factor alpha (TGF alpha), amphiregulin (AR) and heregulin (HRG-beta 1). These polypeptides regulate proliferation in breast cancer cells through interaction with membrane receptors. It has been previously shown that high EGF receptor number correlates with aggressive behavior and increased metastasis in human breast cancer. In the present study, we investigated the association between EGF and EGF-like ligand-induced DNA synthesis and secretion of MMP-9 and MMP-2 in metastatic SKBR-3 and non-metastatic MCF-7 breast cancer cells. Exposure of SKBR-3 cells to EGF or AR induces expression of MMP-9 but has no effect on MMP-2 secretion. In contrast to EGF and AR, HRG had no effect on gelatinase induction. None of the EGF polypeptides had any effect on gelatinase induction in MCF-7 non-metastatic breast cancer cells. While a relatively specific inhibitor of EGF receptor tyrosine kinase, PD 153035, inhibited EGF-, AR- and HRG-induced cell proliferation, it had no effect on MMP-9 induced by EGF and AR. Experimental evidence suggests that signaling mechanisms for cell proliferation and MMP-9 induction are mediated by different pathways down-stream of EGF receptor autophosphorylation or that low levels of EGF-induced signal that escape inhibition are sufficient to induce MMP-9 but unable to support cell proliferation. In addition, our results suggest that EGF and AR may modulate invasion of metastatic breast cancer cells by increasing the expression of MMPs.
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PMID:Epidermal growth factor and amphiregulin up-regulate matrix metalloproteinase-9 (MMP-9) in human breast cancer cells. 909 55

BACKGROUND: An expanded understanding of the biology of breast cancer has led to the identification of the HER-2 receptor as an important growth factor. This receptor possesses intrinsic tyrosine kinase activity and has been associated with aggressive biological behavior and poor clinical outcome. METHODS: Data have been reviewed regarding the role of HER-2 expression as a prognostic variable, as a predictive factor for response to chemotherapy and hormonal therapies, and as a directed therapeutic target for breast cancer. RESULTS: Therapy with a humanized monoclonal antibody to HER-2 (trastuzumab) can be effective treatment in some patients with metastatic breast cancer, either given alone or in combination with some chemotherapeutic agents. Cardiac toxicity limits concurrent use with anthracyclines. Clinical trials will further define optimal combination regimens with this agent, and its value in patients with localized or locally advanced stages. CONCLUSIONS: Trastuzumab is a significant addition to the armamentarium against breast cancer. Standardization of the optimal method to evaluate for HER-2 overexpression is necessary to better define its role as a prognostic, predictor, and therapeutic target in this disease.
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PMID:HER-2 as a Prognostic, Predictive, and Therapeutic Target in Breast Cancer. 1075 52

Abnormal cell signal transduction arising from protein tyrosine kinases has been implicated in the initiation and progression of a variety of human cancers. Over the past 2 decades pharmaceutical and university laboratories have been involved in a tremendous effort to develop compounds that can selectively modulate these abnormal signalling pathways. Targeting receptor tyrosine kinases, especially the epidermal growth factor receptor subfamily, has been at the forefront of this effort as a result of strong clinical data correlating over-expression of these receptors with more aggressive cancers. There are a variety of strategies under development for inhibiting the kinase activity of these receptors, targeting both the extracellular and intracellular domains. Antibody-based approaches, immunotoxins and ligand-binding cytotoxic agents use the extracellular domain for targeted tumour therapy. Small molecule inhibitors target the intracellular catalytic region by interfering with ATP binding, while nonphosphorylatable peptides are aimed at the intracellular substrate binding region. Compounds that inhibit subsequent downstream signals from the receptor by interrupting intracellular protein recognition sequences are also being investigated. In the past 5 years enormous progress has been made in developing tyrosine kinase inhibitor compounds with sufficient potency, bioavailability and selectivity against this subfamily of receptor tyrosine kinases. The anti-HER2 monoclonal antibody, trastuzumab, for patients with metastatic breast cancer is the first of these inhibitor compounds to gain FDA approval. However, preclinical and clinical trials are ongoing with a variety of other monoclonal antibodies, immunotoxins, and small molecule quinazoline and pyrimidine-based inhibitors. Although their cytotoxic and cytostatic potential has been proven, they are not likely to replace standard chemotherapy regimens as single-agent, first-line therapeutics. Instead, their promising additive and synergistic antitumour effects in combination with standard chemotherapeutics suggest that these novel agents will find their greatest utility and efficacy in conjunction with existing anticancer agents.
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PMID:Tyrosine kinase inhibitors targeted to the epidermal growth factor receptor subfamily: role as anticancer agents. 1080 33

The HER2 gene (also known as neu and as c-erb-B2) encodes a 185-kd transmembrane glycoprotein receptor with intrinsic tyrosine kinase activity. HER2 is overexpressed in 25% to 30% of human breast cancers, plays a role in the pathogenesis of breast cancer, and predicts for a worse prognosis in patients with metastatic disease. Trastuzumab (Herceptin; Genentech, Inc, So. San Francisco, CA), a humanized monoclonal antibody that targets the HER2 oncogene receptor, was shown to be active in preclinical models. In initial phase I clinical trials, trastuzumab was found to be safe and to exhibit dose-dependent pharmacokinetics. Three phase II studies of single-agent trastuzumab, which was administered weekly in the outpatient setting, have now been conducted in patients with HER2-overexpressing metastatic breast cancer. In the initial phase II study, the response rate was 11% in a heavily pretreated patient population. In a pivotal follow-up study of single-agent trastuzumab, more than 200 patients who had received at least one prior chemotherapeutic regimen for metastatic disease were entered. Despite a number of unfavorable baseline characteristics, the response rate reported by an independent response evaluation committee was 15%. A more recent study in previously untreated patients has shown a 23% response rate. The median duration of response in these trials has ranged from 6.6 to 9.1 months. In these three phase II studies, trastuzumab has been shown to be safe. The most clinically significant adverse event has been cardiac dysfunction syndrome, which occurred in less than 5% of patients. Trastuzumab is not associated with the other commonly observed side effects of chemotherapy, such as alopecia, mucositis, and neutropenia. The results from these studies demonstrate that trastuzumab is active and safe in patients with metastatic HER2-overexpressing breast cancer.
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PMID:Clinical trials of single-agent trastuzumab (Herceptin). 1104 53

HER2 is a member of tyrosine kinase growth factor receptor family. When activated, it induces an intracellular phosphorylation cascade leading to an increased protein transcription and cellular growth. HER2 is overexpressed or amplified in 20 to 30% of invasive breast cancer where it plays an important role in the natural history of the disease. It is considered a poor prognostic factor and may also play a role as a predictive factor for response to therapy (potential resistance to hormonotherapy or CMF, sensitivity to anthracycline-based therapy). On the other hand, a monoclonal antibody, targetting specifically HER2, Herceptin (trastuzumab) has been developed and has shown a survival benefit in metastatic breast cancer strongly overexpressing HER2. Herceptin is actually "incorporated" in therapeutic algorithms for metastatic breast cancer and is evaluated in adjuvant settings. For all those reasons, the tumor HER2 status should probably be "routinely" tested in order to optimize the management of breast cancer patients. Nevertheless, some points remain to be elucidated, including the optimal methods of detection of HER2 (immunohistochemistry, Fish). One of the priorities for future research is to standardize HER2 testing, in order to reduce false-positive results and false-negative results and to better identify patients who are most likely going to benefit from Herceptin.
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PMID:[Breast cancer and herceptin]. 1112 93

The human epidermal growth factor receptor HER2 or C-erbB-2/neu is a tyrosine kinase membrane receptor, which when activated, induces a phosphorylation cascade in cytoplasmic kinases leading to increased protein transcription and cellular growth. HER2 plays an important role in the biology of breast cancer, an observation that has led to the selection of HER2 as a potential target for breast cancer treatment. Trastuzumab (Herceptin) is the first anti-HER2 monoclonal antibody that has shown a survival benefit in metastatic breast cancer patients with HER2-positive tumours (Norton et al., Proc ASCO 2000 18, 127a (abstract 483)). Tumour HER2 status should no longer be ignored because of its direct implications for the optimal management of breast cancer patients. A high priority for future research is to refine and standardise HER2 testing in order to minimise false-negative results. Furthermore, this procedure would overcome current issues relating to test reproducibility between pathology laboratories and definitions of HER2 positivity. In the meantime, a HER2-positive status on testing using any approved technique has implications for clinical practice (Fig. 1). The treatment algorithm given in Fig. 1 considers the lack of level 1, evidence-based studies that demonstrate convincingly the value of HER2 as a predictive marker for resistance or sensitivity to classic forms of breast cancer therapy (Piccart et al., Eur J Cancer 2000, 36, 1755-1761). In addition, the algorithm incorporates the available data from 1999-2000, which were generated from prospective trials exploring the value of trastuzumab both as a single agent and in combination with chemotherapy.
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PMID:Closing remarks and treatment guidelines. 1116 89

The product of the HER-2/neu proto-oncogene, HER2, is the second member of the human epidermal growth factor receptor (HER) family of tyrosine kinase receptors and has been suggested to be a ligand orphan receptor. Ligand-dependent heterodimerization between HER2 and another HER family member, HER1, HER3 or HER4, activates the HER2 signaling pathway. The intracellular signaling pathway of HER2 is thought to involve ras-MAPK, MAPK-independent S6 kinase and phospholipase C-gamma signaling pathways. However, the biological consequences of the activation of these pathways are not yet completely known. Amplification of the HER2 gene and overexpression of the HER2 protein induces cell transformation and has been demonstrated in 10% to 40% of human breast cancer. HER2 overexpression has been suggested to associate with tumor aggressiveness, prognosis and responsiveness to hormonal and cytotoxic agents in breast cancer patients. These findings indicate that HER2 is an appropriate target for tumor-specific therapies. A number of approaches have been investigated: (1) a humanized monoclonal antibody against HER2, rhuMAbHER2 (trastuzumab), which is already approved for clinical use in the treatment of patients with metastatic breast cancer; (2) tyrosine kinase inhibitors, such as emodin, which block HER2 phosphorylation and its intracellullar signaling; (3) active immunotherapy, such as vaccination; and (4) heat shock protein (Hsp) 90-associated signal inhibitors, such as radicicol derivatives, which induce degradation of tyrosine kinase receptors, such as HER2.
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PMID:Biological and clinical significance of HER2 overexpression in breast cancer. 1118 Jul 65

The human epidermal growth factor receptor HER2 or C-erbB-2/neu is a tyrosine kinase membrane receptor, which when activated, induces a phosphorylation cascade in cytoplasmic kinases leading to increased protein transcription and cellular growth. HER2 plays an important role in the biology of breast cancer, an observation that has led to the selection of HER2 as a potential target for breast cancer treatment. Trastuzumab (Herceptin(R)) is the first anti-HER2 monoclonal antibody that has shown a survival benefit in metastatic breast cancer patients with HER2-positive tumours (Norton et al., Proc ASCO 2000 18, 127a (abstract 483)). Tumour HER2 status should no longer be ignored because of its direct implications for the optimal management of breast cancer patients. A high priority for future research is to refine and standardise HER2 testing in order to minimise false-negative results. Furthermore, this procedure would overcome current issues relating to test reproducibility between pathology laboratories and definitions of HER2 positivity. In the meantime, a HER2-positive status on testing using any approved technique has implications for clinical practice (Fig. 1). The treatment algorithm given in Fig. 1 considers the lack of level 1, evidence-based studies that demonstrate convincingly the value of HER2 as a predictive marker for resistance or sensitivity to classic forms of breast cancer therapy (Piccart et al., Eur J Cancer 2000, 36, 1755-1761). In addition, the algorithm incorporates the available data from 1999-2000, which were generated from prospective trials exploring the value of trastuzumab both as a single agent and in combination with chemotherapy.
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PMID:Closing remarks and treatment guidelines. 1134 98

Several agents that target one or more members of the erbB family of receptor tyrosine kinases are currently undergoing clinical investigation. The monoclonal antibody trastuzumab has been shown effective in erbB2-expressing metastatic breast cancer when administered as a single agent or in combination with cytotoxic chemotherapy. Toxicities associated with trastuzumab include infusion-related fever and chills, hypersensitivity reactions, and congestive heart failure. C225 is a monoclonal antibody directed against the epidermal growth factor receptor, which has shown encouraging antitumor activity in early clinical development. The orally active tyrosine kinase inhibitors show encouraging antitumor activity in preclinical models and early clinical trials. Members of this class currently in clinical development include ZD1839, OSI-774, and CI-1033. Evidence to date suggests that the major role for erbB receptor-targeting drugs will be in combined therapy to enhance response to cytotoxic drugs, and in long-term monotherapy to maintain response and prevent disease progression or recurrence.
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PMID:Anticancer therapy targeting the erbB family of receptor tyrosine kinases. 1170 98

Overexpression of the HER2/neu oncogene (also known as c-erbB2) is a frequent molecular event in multiple human cancers, including breast and ovarian cancer. Patients with cancer that overexpress HER2/neu are associated with unfavorable prognosis, shorter relapse time, and low survival rate. Treatments that target HER2/neu expression in cancer cells have been shown to be useful strategies to significantly reverse the malignancy induced by HER2/neu overexpression. The humanized anti-HER2/neu antibody, trastuzumab (Herceptin; Genentech, Inc, South San Francisco, CA) has proven to be effective in clinical trials in patients with metastatic breast cancer. In addition, tyrosine kinase inhibitors such as emodin can also target the HER2/neu oncogenic activity. Emodin treatment inhibits HER2/neu tyrosine kinase activity and preferentially suppresses the transformation of HER2/neu-overexpressing breast cancer cells. Emodin also sensitizes HER2/neu-overexpressing cancer cells to chemotherapeutic agents, including cisplatin, doxorubicin, etoposide, and paclitaxel. Alternatively, HER2/neu overexpression can be repressed by attenuating the promoter activity of the HER2/neu gene. We have identified a number of potent transcriptional regulators, including the ets family member PEA3 and the adenovirus type 5 E1A, which are able to repress HER2/neu gene expression. Expression of these transcriptional regulators resulted in downregulation of HER2/neu promoter activity and reversed the transformed phenotype of the cancer cells in vitro. In vivo studies show that these HER2/neu repressors can act therapeutically as tumor suppressor genes for tumors that overexpress HER2/neu. These preclinical studies clearly indicate that transcriptional repressors that downregulate HER2/neu can be effective regimens for cancer treatment in a gene therapy format. More importantly, the tumor-free survival rate of treated animals is dramatically increased under nontoxic doses compared with untreated animals. A phase I clinical trial using E1A-liposome in breast and ovarian patients has recently been completed. Following treatment, we observed downregulation of the HER2/neu protein accompanied by E1A expression in both cancer and noncancer cells. Numbers of tumor cells in the pleural effusion or ascites were found to be dramatically reduced after treatment. Furthermore, apoptosis was strongly induced in the tumor cells. A phase II study has been started to further evaluate therapeutic efficacy and tumor suppression mechanisms of E1A. These studies show the clinical potential of targeting HER2/neu in cancer therapy.
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PMID:Targeting HER2: recent developments and future directions for breast cancer patients. 1177 2


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