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)

We examined expression of N-methylpurine-DNA glycosylase (MPG), a DNA repair enzyme that removes N-alkylpurine damage, in normal, malignant, and immortalized breast epithelial cells, and breast cancer cell lines (MDA-MB-231, MCF7, T47D). Northern analysis showed increased expression in cancer versus normal breast epithelial cells (2-24-fold). Southern blots revealed no gene amplification or polymorphisms. Immunofluorescence, immunohistochemistry, and Western blot analysis demonstrated increased MPG protein expression in the tumor cells that correlated with elevated glycosylase activity. Since MPG overexpression has been shown to be paradoxically associated with increased susceptibility to DNA damage, up-regulation of this gene may suggest a functional role in breast carcinogenesis.
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PMID:Altered expression of the DNA repair protein, N-methylpurine-DNA glycosylase (MPG) in breast cancer. 968 56

17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is an ansamycin antibiotic that binds to a conserved pocket in Hsp90 and induces the degradation of proteins that require this chaperone for conformational maturation. 17-AAG causes a retinoblastoma (RB)-dependent G1 block in cancer cells and is now in clinical trial. In breast cancer cells, G1 block is accompanied by differentiation and followed by apoptosis. The differentiation is characterized by specific changes in morphology and induction of milk fat proteins and lipid droplets. In cells lacking RB, neither G1 arrest nor differentiation occurs; instead, they undergo apoptosis in mitosis. Introduction of RB into these cells restores the differentiation response to 17-AAG. Inhibitors of the ras, mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways cause accumulation of milk fat proteins and induction of lipid droplets when associated with G1 arrest but do not cause morphological changes. Thus, regulation of Hsp90 function by 17-AAG in breast cancer cells induces RB-dependent morphological and functional mammary differentiation. G1 arrest is sufficient for some but not all aspects of the phenotype. Induction of differentiation may be responsible for some of the antitumor effects of this drug.
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PMID:Inhibition of heat shock protein 90 function by ansamycins causes the morphological and functional differentiation of breast cancer cells. 1130 72

Ansamycin antibiotics, such as 17-allylaminogeldanamycin (17-AAG), bind to Hsp90 and regulate its function, resulting in the proteasomal degradation of a subset of signaling proteins that require Hsp90 for conformational maturation. HER2 is a very sensitive target of these drugs. Ansamycins cause RB-dependent G1 arrest that is associated with loss of D-cyclins via a PI3 kinase, Akt dependent pathway. Downregulation of D-cyclin was due, in part, to loss of Akt expression in response to drug. Moreover, in HER2 overexpressing breast cancer cells, 17-AAG caused rapid inhibition of Akt activity prior to any change in Akt protein. Ansamycins caused rapid degradation of HER2 and a concomitant loss in HER3 associated PI3 kinase activity. This led to a loss of Akt activity, dephosphorylation of Akt substrates, and loss of D-cyclin expression. Introduction into cells of a constitutively membrane bound form of PI3 kinase prevented the effects of the drug on Akt activity and D-cyclins. Thus, in breast cancer cells with high HER2, Akt activation by HER2/HER3 heterodimers is required for D-cyclin expression. In murine xenograft models, non-toxic doses of 17-AAG markedly reduced the expression of HER2 and phosphorylation of Akt and inhibited tumor growth. Thus, pharmacological inhibition of Akt activation is achievable with ansamycins and may be useful for the treatment of HER2 driven tumors.
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PMID:Ansamycin antibiotics inhibit Akt activation and cyclin D expression in breast cancer cells that overexpress HER2. 1185 Aug 35

Breast cancers with high expression of HER2 are associated frequently with aggressive, poor prognosis disease and resistance to chemotherapy-induced apoptosis. Geldanamycin and its less toxic analogue, 17- (allylamino)-17-demethoxygeldanamycin (17-AAG) are ansamycin antibiotics that bind to a highly conserved pocket in the hsp 90 chaperone protein and inhibit its function. Hsp 90 is required for the refolding of proteins during environmental stress and the conformational maturation of certain signaling proteins. Among the most sensitive targets of 17-AAG are the HER kinases. Therefore, tumors that are dependent on these kinases may be especially sensitive to 17-AAG either alone or in combination with chemotherapy. In this study we demonstrate that cells that overexpress HER2 are 10-100-fold more sensitive to 17-AAG than cancer cells expressing low levels of HER2. We found that HER2 is degraded in several cell lines, but only cell lines with high levels of HER2 are sensitive to the drug. The effects of 17-AAG on growth and apoptosis are because of inhibition of signaling through HER2-HER3, phosphatidylinositol 3'- kinase. The absence of HER3 and the introduction of constitutively active p110alpha rendered cells with high HER2 expression more resistant to 17-AAG. These findings suggest that 17-AAG may be useful for the treatment of breast cancer cells with high levels of HER2. However, the overexpression of HER2 alone may not be predictive of response, because the coexpression of HER3 and the activation of phosphatidylinositol 3'-kinase may play a crucial role in the response of these cells to 17-AAG and other drugs directed against HER2. These observations have important clinical implications because they may help to identify patients that are most likely to benefit from 17-AAG and may explain resistance to Herceptin as seen in many patients.
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PMID:Degradation of HER2 by ansamycins induces growth arrest and apoptosis in cells with HER2 overexpression via a HER3, phosphatidylinositol 3'-kinase-AKT-dependent pathway. 1203 25

Single strand conformation polymorphism (SSCP) analysis was performed on genomic DNA from 97 human breast cancer samples and 10 breast cell lines to screen for mutations in the single exon C/EBPD gene. Three C --> T transitions resulting in silent mutations were detected in three individual breast cancer samples. One breast cancer sample also contained a G --> T transversion (Q253H). The SUM-52PE cell line contained an A --> T transversion (AAG --> TAG) resulting in a nonsense mutation (K180Stop). All mutations identified in genomic DNA isolates were in highly conserved regions of the C/EBPD gene. This study indicates that mutational alterations in the coding region of the C/EBPD gene are relatively uncommon in human breast cancer.
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PMID:Detection of base sequence changes in the CEBPD gene in human breast cancer cell lines and primary breast cancer isolates. 1262 88

ERBB2 increases the sensitivity of breast cancer cells to the HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG). This has been attributed to the disruption of ERBB3/ERBB2 heterodimers that maintain a crucial cell survival signal via phosphatidylinositol 3-kinase/AKT. ERBB2 confers a poor clinical outcome in medulloblastoma, the most common malignant pediatric brain tumor. Here, we show that medulloblastoma cell sensitivity to 17-AAG is directly related to ERBB2 expression level. Furthermore, overexpression of exogenous ERBB2 in these cells induces spontaneous homodimerization, further enhancing cell sensitivity to 17-AAG. In contrast to breast cancer cells, this increased sensitivity to 17-AAG does not result from cell dependence on AKT1 activity. Rather, we show that 17-AAG generates a dose- and time-dependent increase in MEK/ERK signaling that is required for the drug to inhibit the proliferation of medulloblastoma cells and that ERBB2 sensitizes medulloblastoma cells to 17-AAG by up-regulating basal MEK/ERK signaling. We further show that down-regulation of MEK1 activity markedly reduces the sensitivity of medulloblastoma, breast, and ovarian cancer cells to 17-AAG, whereas expression of a constitutively active MEK1 potentiates the activity of 17-AAG against these cells. Therefore, intact MEK/ERK signaling may be required for optimal 17AAG activity against a variety of tumor cell types. These data identify a new mechanism by which 17-AAG inhibits the proliferation of cancer cells. Defining the precise mode of action of these agents within specific tumor cell types will be crucial if this class of drugs is to be efficiently developed in the clinic.
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PMID:Medulloblastoma sensitivity to 17-allylamino-17-demethoxygeldanamycin requires MEK/ERKM. 1270 19

The phosphatidylinositol 3'-kinase/Akt pathway is activated frequently in human cancer, and has been implicated in tumor proliferation, cell survival, and resistance to apoptotic stimuli. Akt forms a complex with heat shock protein (Hsp) 90 and Cdc37, and inhibitors of Hsp90 cause Akt degradation. 17-allylamino-17-demethoxygeldanamycin (17-AGG) is an Hsp90 inhibitor currently in Phase I clinical trial. 17-AAG inhibits Akt activation and expression in tumors, and has antitumor activity in breast cancer xenografts. The combination of 17-AAG and Taxol is synergistic, and 17-AAG sensitizes tumor cells to Taxol-induced apoptosis in a schedule-dependent manner. Transfection of membrane-bound p110 PI3k prevented 17-AAG inactivation of Akt and abrogated the enhancement of Taxol-induced apoptosis caused by the drug. 17-AAG and Taxol could be administered together at their maximally tolerated doses to tumor-bearing mice. Doses of 17-AAG that induce HER2 degradation and cause Akt inactivation but have no single agent activity were effective in sensitizing tumors to Taxol. Enhancement was schedule-dependent and maximal when Taxol and 17-AAG were administered on the same day. These results suggest that Hsp90 inhibitors can effectively suppress Akt activity in animal models of human cancer at nontoxic doses, thus sensitizing tumor cells to proapoptotic stimuli.
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PMID:Inhibition of heat shock protein 90 function down-regulates Akt kinase and sensitizes tumors to Taxol. 1272 31

A whole-body physiologically-based model was developed to describe the pharmacokinetics of the ansamycin benzoquinone antibiotic 17-(allylamino)-17-demethoxygeldanamycin (17AAG) and its active metabolite 17-(amino-)-17-demethoxygeldanamycin (17AG) in blood, normal organs (lung, brain, heart, spleen, liver, kidney, skeletal muscle) and implanted human tumor xenograft in nude mice. The distribution of 17 AAG in all organs was described by diffusion-limited exchange models, while that of 17 AG was described by perfusion-limited models. The intrinsic clearances of 17AAG and 17AG in the liver were uniquely identified using local models and were estimated to be 4.93 ml/hr and 3.34 ml/hr. It was also estimated that the formation of 17AG in liver accounted for 40% of the 17AAG intrinsic clearance. The model for the distribution of both 17AAG and 17AG in the human breast cancer tumor xenograft included vascular, interstitial and intracellular compartments, which yielded the predicted cellular concentrations of 17AAG and 17AG two to three times higher than the corresponding whole tissue measurements at steady state. Estimates of the vascular-interstitial permeability surface-area product were similar for 17AAG and 17AG (0.23 ml/hr and 0.26 ml/hr). However, the interstitial to cellular transport rate of 17AG was three-fold greater than that of 17AAG, which resulted in the preferential uptake of 17AG over 17AAG in tumor. Indirect response models were developed to describe the combined action of 17AAG and 17AG on the onco-proteins Raf-1 and p185erbB2 in tumor. The half-life of endogenous protein turnover was estimated to be 22.6 hr for Raf-1 and 8.6 hr for p185erbB2, and both were comparable to corresponding values measured in vitro. A model for the molecular chaperon heat shock proteins HSP70 and HSP90 was developed based on the molecular mechanism of heat shock auto-regulation and the action of 17AAG and 17AG on these proteins. The model provided in vivo estimates of endogenous HSP70 and HSP90 turnover. In modeling pharmacokmetics and pharmacodynamics, Bayesian inference was employed to estimate the kinetic, physiological and molecular parameters when prior information was available.
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PMID:Physiologically-based pharmacokinetics and molecular pharmacodynamics of 17-(allylamino)-17-demethoxygeldanamycin and its active metabolite in tumor-bearing mice. 1457 91

Rapidly evolving insights into the specific molecular genetic abnormalities that drive the growth and metastasis of breast cancer have led to the development of targeted therapeutics that do not rely on the generalized disruption of DNA metabolism and cell division for activity. Of particular interest are inhibitors of cellular signal transduction pathways involving tyrosine kinases as well as selective modulators of steroid hormone signaling, histone acetylation, angiogenesis and tumor cell apoptosis. Unique within this array of promising new agents, however, are compounds that target heat shock protein 90 (Hsp90). This molecular chaperone associates with a distinct, but surprisingly diverse, set of proteins that are referred to as Hsp90 client proteins. Hsp90 binds to these clients, and plays a key role in regulating their stability and function. Many of the proteins chaperoned by Hsp90 are involved in breast cancer progression and resistance to therapy, including the estrogen receptor, receptor tyrosine kinases of the erbB family, Akt, and mutant p53. Several small molecule inhibitors of Hsp90 have been identified that can deplete cellular levels of multiple oncogenic client proteins simultaneously by enhancing their ubiquitination and proteasome-mediated degradation. The activity of Hsp90 inhibitors has been well validated in preclinical breast cancer models, both in single-agent studies and in combination with conventional chemotherapy. One of these inhibitors, 17-allylamino, 17-demethoxygeldanamycin (17-AAG, NSC 330507) has recently completed phase I testing. The agent was well tolerated at drug exposures that were shown to cause modulation of Hsp90 client protein levels. Given the redundancy and complexity of the molecular abnormalities present in most breast cancers, the ability of Hsp90 inhibitors to alter the activity of multiple oncogenic targets may prove of unique therapeutic benefit.
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PMID:Hsp90: an emerging target for breast cancer therapy. 1526 96

In an effort to improve the efficacy of cancer chemotherapy by intervening into the cellular responses to chemotherapeutic change, we have used adenoviral overexpression of N-methylpurine DNA glycosylase (MPG or ANPG/AAG) in breast cancer cells to study its ability to imbalance base excision repair (BER) and sensitize cancer cells to alkylating agents. Our results show that MPG-overexpressing cells are significantly more sensitive to the alkylating agents methyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, methylnitrosourea, dimethyl sulfate, and the clinical chemotherapeutic temozolomide. Sensitivity is further increased through coadministration of the BER inhibitor methoxyamine, which covalently binds abasic or apurinic/apyrimidinic (AP) sites and makes them refractory to subsequent repair. Methoxyamine reduction of cell survival is significantly greater in cells overexpressing MPG than in control cells, suggesting a heightened production of AP sites that, if made persistent, results in increased cellular toxicity. We further explored the mechanism of MPG-induced sensitivity and found that sensitivity was associated with a significant increase in the number of AP sites and/or single-strand breaks in overexpressing cells, confirming a MPG-driven accumulation of toxic BER intermediates. These data establish transient MPG overexpression as a potential therapeutic approach for increasing cellular sensitivity to alkylating agent chemotherapy.
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PMID:Transient adenoviral N-methylpurine DNA glycosylase overexpression imparts chemotherapeutic sensitivity to human breast cancer cells. 1529 78


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