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)

HER-2 is a tyrosine kinase receptor which is overexpressed in 20-25% of breast cancer patients and is associated with poor prognosis. Trastuzumab, a humanized monoclonal antibody directed against the HER-2 receptor, used alone or in combination with chemotherapy, has shown significant clinical benefit in improving survival in metastatic patients, as well as halving the recurrence rate and improving survival in early breast cancer. Even with these impressive results, the reality is that not all patients will benefit form this therapy, and in those who do, resistance to trastuzumab can often develop within 1 year of treatment initiation. Beyond trastuzumab therapy, a "second wave" of monoclonal antibodies and tyrosine kinase inhibitors has emerged. These drugs have variable properties including: 1) dual inhibition against EGFR and HER-2, such as lapatinib, HKI-272 and pertuzumab; 2) anti-angiogenesis such as bevacizumab and pazopanib; 3) anti-mTOR action such as Temsirolimus; and 4) anti-Hsp90 such as 17-AAG. When used in combination with trastuzumab, or with cytotoxic chemotherapy, or as single agents, these new anti-HER-2 strategies bear the potential of arresting the tumorigenesis process. In this article, we present the current strategies in the treatment of breast cancer patients who overexpress HER-2, with particular focus on new tyrosine kinase inhibitors that can be used in combination with or after trastuzumab therapy.
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PMID:HER-2 positive breast cancer: what else beyond trastuzumab-based therapy? 1853 32

We have recently shown that macrophage-stimulating protein (MSP) promotes the invasion of recepteur d'origine nantais (RON), a tyrosine kinase receptor-positive MDA-MB-231, MDA-MB-468 breast cancer cells, and also identified the regulatory elements required for RON gene expression. In this report, we have analyzed the efficacy of a chemopreventive agent, curcumin, in blocking RON tyrosine kinase-mediated invasion of breast cancer cells. Reverse transcription-PCR and Western analysis indicated the down-regulation of the RON message and protein, respectively, in MDA-MB-231 and MDA-MB-468 cells. Significantly, curcumin-mediated inhibition of RON expression resulted in the blockade of RON ligand, MSP-induced invasion of breast cancer cells. We have identified two putative nuclear factor-kappaB p65 subunit binding sites on the RON promoter. Using chromatin immunoprecipitation analysis and site-directed mutagenesis of the RON promoter, we have confirmed the binding of p65 to the RON promoter. Our data show that curcumin reduces RON expression by affecting p65 protein expression and transcriptional activity. Treatment of MDA-MB-231 cells with pyrrolidine dithiocarbamate, an inhibitor of p65, or small interfering RNA knockdown of p65, blocked RON gene expression and MSP-mediated invasion of MDA-MB-231 cells. This is the first report showing the regulation of human RON gene expression by nuclear factor-kappaB and suggests a potential therapeutic role for curcumin in blocking RON tyrosine kinase-mediated invasion of carcinoma cells.
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PMID:Curcumin blocks RON tyrosine kinase-mediated invasion of breast carcinoma cells. 1859 18

Inhibitors of fatty acid synthase (FASN), a key enzyme involved in the anabolic conversion of dietary carbohydrates to fat in mammals, are receiving increasingly more attention as they may provide therapeutic moieties for the treatment of human malignancies. Natural compounds, such as the green tea polyphenol epigallocatechin-3-gallate, have been shown to induce anti-cancer effects by suppressing FASN, which may account for the epidemiologically observed inverse correlation between green-tea drinking and cancer risk in Oriental populations. Since extra-virgin olive oil (EVOO)-derived phenolics have been suggested to possess biological activities that may explain the health-promoting effects of the 'Mediterranean diet', we evaluated their effects on the expression of FASN protein in human breast epithelial cell lines. First, we developed a reverse phase protein microspot array (RPPA) capable of rapidly assessing the relative amount of FASN protein in whole lysates from cultured human cells. Then we tested the effects of phenolic fractions from EVOO and its main constituents including single phenols (i.e. tyrosol, hydroxytyrosol, vanillin), phenolic acids (i.e. caffeic acid, p-coumaric acid, vanillic acid, ferulic acid, elenolic acid), lignans (i.e. 1-[+]-pinoresinol, 1-[+]-acetoxy-pinoresinol), flavonoids (i.e. apigenin, luteolin), or secoiridoids (i.e. deacetoxyoleuropein aglycone, ligstroside aglycone, oleuropein glycoside, oleuropein aglycone) on FASN protein expression. EVOO polyphenols lignans, flavonoids and secoiridoids were found to drastically suppress FASN protein expression in HER2 gene-amplified SKBR3 breast cancer cells. Equivalent results were observed in MCF-7 cells engineered to overexpress the HER2 tyrosine kinase receptor, a well-characterized up-regulator of FASN expression in aggressive sub-types of cancer cells. EVOO-derived lignans, flavonoids and secoiridoids were significantly more effective than the mono-HER2 inhibitor trastuzumab ( approximately 50% reduction) and as effective as the dual HER1/HER2 tyrosine kinase inhibitor lapatinib (> or =95% reduction) at suppressing high-levels of FASN protein in HER2-overexpressing SKBR3 and MCF-7/HER2 cells. EVOO single phenols and phenolic acids failed to modulate FASN expression in SKBR3 and MCF-7/HER2 cells. These findings reveal for the first time that phenolic fractions, directly extracted from EVOO, may induce anti-cancer effects by suppressing the expression of the lipogenic enzyme FASN in HER2-overexpressing breast carcinoma cells, thus offering a previously unrecognized mechanism for EVOO-related cancer preventive effects.
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PMID:Analyzing effects of extra-virgin olive oil polyphenols on breast cancer-associated fatty acid synthase protein expression using reverse-phase protein microarrays. 1881 48

EGFRvIII is a cancer-specific epidermal growth factor tyrosine kinase receptor mutation, expressed in different kinds of cancer, in particular ovarian, glioblastomas, and breast cancer. A peptide, PEPHC1, has previously been shown to bind selectively to EGFRvIII. An alanine scan was performed to identify the amino acid residues important for binding of PEPHC1 to EGFRvIII. The results indicate that the amino acid residues at the N-terminus of PEPHC1 are essential for the binding to the mutated receptor. One analog, [Ala(12)]PEPHC1, showed higher selective binding to EGFRvIII than PEPHC1. On the basis of these results, six truncated peptide analogs derived from the N-terminus of PEPHC1, H-HFIIL-NH2, H-HFIILG-NH2, H-HFIILGF-NH2, H-HFIILGFM-NH2, H-HFLIIGFMR-NH2, and H-HFLIIGFMRR-NH2 were synthesized and tested in the same manner. We observed that H-HFIIL-NH2 and H-HFIILG-NH2 showed almost threefold lower binding to the mutated receptor than PEPHC1, whereas the remainder showed 25% lower binding. The secondary structure of the PEPHC1 analogs was investigated by far UV circular dichroism spectroscopy and their binding correlated with various structural parameters such as charge, mean hydrophobicity (<H>), and mean hydrophobic moment (<mu(H)>). This work provides data, which will be useful in the development of novel peptide-based ligands for EGFRvIII-targeted diagnostics and therapy. This work was in part presented at the 17th International Symposium on Radiopharmaceutical Sciences, April 2007, Aachen, Germany.
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PMID:Identification of amino acid residues in PEPHC1 important for binding to the tumor-specific receptor EGFRvIII. 1884 73

It has been over 20 years since the discovery of the human epidermal growth factor receptor 2 (HER2), a tyrosine kinase receptor that is a potent oncoprotein in breast and other cancers and has become an opportune target for therapy. HER2 plays a critical role in normal development, forming homodimers or heterodimers with other HER family members and triggering downstream signaling cascades controlling proliferation, cell survival, and apoptosis. However, amplification of the HER2 gene in cancer cells results in overexpression of HER2 receptors on the cell surface, leading to excessive and dysregulated signaling. HER2-driven signaling also upregulates transcription factors that act on the HER2 promoter, increasing its expression. In breast cancer, HER2 is gene amplified in 20%-25% of primary tumors and is associated with a more aggressive phenotype and poorer prognosis. The key role HER2 plays in tumorigenesis makes it an ideal target for therapy. Trastuzumab, a monoclonal antibody against HER2, inhibits downstream signaling and has proven to be effective against HER2-overexpressing metastatic breast cancer both as a single agent and in combination with chemotherapy. Seminal clinical trial data also show that the use of adjuvant trastuzumab in combination with chemotherapy or as a single agent after chemotherapy significantly increases disease-free and overall survival. Lapatinib, a dual tyrosine kinase inhibitor against HER1 and HER2, has been approved in combination with capecitabine for HER2-overexpressing advanced or metastatic breast cancer, which has progressed following previous anthracycline, taxane, and trastuzumab therapy. Other HER2-targeting strategies are also under active investigation.
Clin Breast Cancer 2008 Oct
PMID:Unraveling the biologic and clinical complexities of HER2. 1895 52

Human epidermal growth factor receptor type 2 (HER2) is a transmembrane tyrosine kinase receptor, which is overexpressed in a large fraction of breast, ovarian, urinary bladder and a number of other carcinomas. Overexpression of HER2 is associated with poor prognosis. Treatment of patients with HER2-expressing breast cancer with a humanized anti-HER2 monoclonal antibody trastuzumab has resulted in improved survival. Several kinds of other anti-HER2 therapies are under development. Radionuclide molecular imaging of HER2 expression may influence patient management by selecting patients, who would benefit form anti-HER2 therapy. Other applications, such as therapy response monitoring and follow-up are also possible. In this case, the use of radionuclide imaging may overcome problems associated with biopsies, including sampling errors and discordance of expression between primary tumors and metastases. Important preconditions for development of a successful tracer for radionuclide imaging are high affinity of a targeting agent and suitable chemistry of labeling. The paper reviews information concerning major classes of HER2-targeting agents, including full-length monoclonal antibodies, their enzymatically produced fragments, engineered immunoglobulin based tracers, and alternative high affinity binders. Available information suggests that Affibody molecules or other small non-immunoglobulin based tracers have the best potential for development of high-contrast imaging agents for visualization of HER2 in vivo.
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PMID:Imaging of HER-2 overexpression in tumors for guiding therapy. 1899 15

There is strong clinical evidence that trastuzumab, a monoclonal antibody targeting the human epidermal growth factor receptor (HER) two tyrosine kinase receptor, is an important component of first-line treatment of patients with HER2-positive metastatic breast cancer. In particular the combination with taxanes and vinorelbine has been established. In the preoperative setting inclusion of trastuzumab has significantly increased the pathological complete response rate. Results from large phase III trials evaluating adjuvant therapy in HER2-positive early breast cancer indicate that the addition of trastuzumab to chemotherapy improves disease-free and overall survival. The use of lapatinib, a dual tyrosine kinase inhibitor of both HER1 and HER2, in combination with capecitabine in the second-line treatment of HER2-positive patients with metastatic breast cancer previously treated with trastuzumab has been established. There is modest, but still insufficient, support that the compound passes the blood-brain barrier. Several trials are ongoing both in the adjuvant and metastatic settings and we have to await the results of these to clarify the role of trastuzumab and lapatinib. The clinical problem of tumours developing resistance to HER2-directed therapy is becoming increasingly important. Several issues about optimal selection of patients, prevention of resistance and use of different treatment options are still unresolved. In this article, we summarise the current knowledge on clinical evidence of HER2-directed therapy and the potential mechanisms of underlying resistance, including the possible clinical implications and review new therapeutic options.
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PMID:HER2-targeted therapy in breast cancer. Monoclonal antibodies and tyrosine kinase inhibitors. 1900 49

Depending on their structure, some polyphenols (e.g. flavonoids) abundantly found in plant-derived beverages such as green tea can efficiently inhibit tyrosine kinase and serine/threonine kinase activities. Extra-virgin olive oil (EVOO - the juice of the olive obtained solely by pressing and consumed without any further refining process) is unique among other vegetable oils because of the high level of naturally occurring phenolic compounds. We explored the ability of EVOO polyphenols to modulate HER2 tyrosine kinase receptor-induced in vitro transformed phenotype in human breast epithelial cells. Using MCF10A normal breast epithelial cells retrovirally engineered to overexpress the wild-type sequence of human HER2, we further determined the relationship between chemical structures of EVOO-derived phenolics and their inhibitory activities on the tyrosine kinase activity of the HER2 oncoprotein. When the activation (phosphorylation) status of HER2 was semi-quantitatively measured the secoiridoids blocked HER2 signaling by rapidly reducing the activation status of the 1248 tyrosine residue (Y1248), the main autophosphorylation site of HER2. EVOO-derived single phenols tyrosol and hydroxytyrosol and the phenolic acid elenolic acid failed to significantly decrease HER2 tyrosine kinase activity. The anti-HER2 tyrosine kinase activity IC50 values were up to 5-times lower in the presence of EVOO-derived lignans and secoiridoids than in the presence of EVOO-derived single phenols and phenolic acids. EVOO polyphenols induced strong tumoricidal effects by selectively triggering high levels of apoptotic cell death in HER2-positive MCF10A/HER2 cells but not in MCF10A/pBABE matched control cells. EVOO lignans and secoiridoids prevented HER2-induced in vitro transformed phenotype as they inhibited colony formation of MCF10A/HER2 cells in soft-agar. Our current findings not only molecularly support recent epidemiological evidence revealing that EVOO-related anti-breast cancer effects primarily affect the occurrence of breast tumors over-expressing the type I receptor tyrosine kinase HER2 but further suggest that the stereochemistry of EVOO-derived lignans and secoiridoids might provide an excellent and safe platform for the design of new HER2 targeted anti-breast cancer drugs.
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PMID:Extra-virgin olive oil polyphenols inhibit HER2 (erbB-2)-induced malignant transformation in human breast epithelial cells: relationship between the chemical structures of extra-virgin olive oil secoiridoids and lignans and their inhibitory activities on the tyrosine kinase activity of HER2. 1908 76

We report here, the design and synthesis of a positional scanning synthetic combinatorial library for the identification of novel peptide ligands targeted against the cancer-specific epidermal growth factor tyrosine kinase receptor mutation variant III (EGFRvIII). This receptor is expressed in several kinds of cancer, in particular, ovarian, glioblastomas, and breast cancer, but not in normal tissue. The library consisted of six individual positional sublibraries in the format, H-O(1-6)XXXXX-NH(2), O being one of the 19 proteinogenic amino acids (cysteine omitted) and X an equimolar mixture of these. The library consisted of 114 mixtures in total. Using a biotin-streptavidin assay, the binding of each sublibrary to NR6M, NR6W-A, and NR6 cells was tested. These cells express EGFRvIII, EGFR, and neither of the receptors, respectively. The result from each sublibrary was examined to identify the most active amino acid residue at each position. On the basis of this knowledge, eight peptides were synthesized and tested for binding to EGFRvIII. We identified one peptide, H-FALGEA-NH(2), that showed more selective binding to the mutated receptor than the EGFRvIII specific peptide PEPHC1. This study demonstrates the value of using mixture-based combinatorial positional scanning libraries for the identification of novel peptide ligands targeted against the cancer-specific EGFRvIII. Our best candidate H-FALGEA-NH(2) will be radioactively labeled and evaluated as an imaging agent for positron emission tomography investigation for diagnosis, staging, and monitoring of therapy of various types of cancer.
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PMID:Identification of novel peptide ligands for the cancer-specific receptor mutation EFGRvIII using a mixture-based synthetic combinatorial library. 1910 25

HER2 is a transmembrane tyrosine kinase receptor in the EGFR (epidermal growth factor receptor) family. The role of HER2 has been most thoroughly studied in breast cancer, in which constitutively active HER2 is overexpressed in 18-22% of cases and is correlated with a poor prognosis. Hence, effective inhibition of the constitutive HER2 signaling in cancer cells has been a major goal in the design of therapies. Therapeutic targeting of HER2 with humanized antibodies such as trastuzumab (Herceptin TM, Genentech) South San Francisco, CA) has proven to be an effective approach for the treatment of breast cancer cells that over-express HER2. The encouraging results of trastuzumab in patients with metastatic and early breast cancer diseases have prompted the evaluation of new HER2 inhibitors for increasing the potential for combinatorial therapies. This review will focus on patents that target HER2 in anti-cancer treatment.
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PMID:Anti-HER2 treatment and breast cancer: state of the art, recent patents, and new strategies. 1914 84


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