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 response profiles of 36 para-substituted diphenylethylenes (DPEs) and triphenylacrylonitriles (TPEs) have been compared by multivariate analysis. The responses measured were (a) relative binding affinity (RBA) for the cytosol estrogen receptor (ER), (b) ability to promote the growth of the human MCF7 breast cancer cell-line, (c) cytotoxicity in MCF7 cells, and (d) ability to stimulate or inhibit protein kinase C (PKC) III activity under three different conditions of enzyme activation. The prime object of the analysis was to observe the simultaneous influence of diverse combinations of substituents on all these in vitro responses. To do this, the minimum spanning tree (MST) method was used to organize the molecules into a network in which proximate molecules are closely related with regard to their responses whereas remote molecules are distinct. The MST of this population of molecules had four main branches. E2 and its TPE mime were located in a central position within the trunk whereas the tips of the branches tended toward molecules of different specificity, i.e., cytotoxic molecules that bind to ER and interfere with PKC, noncytotoxic molecules that also bind to ER and interfere with PKC but promote cell growth, molecules only active on PKC, and molecules active on all parameters except PKC stimulation. A parallel MST analysis of the relationships among the response parameters themselves confirmed previous conclusions: For this population of molecules, RBAs for ER are fairly closely related to ability to promote MCF7 cell growth and only little to cytotoxicity (Bignon et al. J. Med. Chem. 1989, 32, 2092). Cytotoxicity is much more clearly correlated with inhibition of diacylglycerol-stimulated PKC activity than with RBAs for ER. PKC inhibition differs substantially depending upon whether the substrate is H1 histone or protamine sulfate.
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PMID:Multivariate analysis by the minimum spanning tree method of the structural determinants of diphenylethylenes and triphenylacrylonitriles implicated in estrogen receptor binding, protein kinase C activity, and MCF7 cell proliferation. 173 50

It has been suggested that protein kinase C (PKC) plays a role in multidrug resistance (MDR). In this study we assayed PKC activity in MOLT-3 human acute lymphoblastic leukemia cells and found an approximately 50% decrease in activity in MDR sublines made resistant to the lipophilic antifolate trimetrexate, when compared with trimetrexate-sensitive parent cells. The PKC activity of a methotrexate-resistant subline without MDR (MOLT-3/MTX10,000) was identical to that of parent cells. Although a downward trend was noted in PKC activity in the membrane fraction of cells with increasing trimetrexate resistance, there was no absolute correlation between the degree of MDR and the relative decrease in PKC activity. Using the same method, we also confirmed an over 6-fold increase in PKC activity in the MDR human breast cancer subline MCF-7/DOXR when compared with the sensitive parent cell line, MCF-7/WT. Because of this divergent relationship between relative PKC activity and MDR, we tested the effect of PKC inhibition and activation on drug resistance. The PKC inhibitor staurosporine, at both subtoxic and toxic concentrations as well as at concentrations shown to be inhibitory to PKC, failed to increase drug resistance of parent and resistant MOLT-3 cells and decrease drug resistance of MCF-7/WT and MCF-7/DOXR cells. Short-term exposure to 3-phorbol-12-myristate-13-acetate, which activated PKC 7.0-fold and 4.7-fold, respectively, in the membrane of MOLT-3 and resistant cells, resulted in small (1.3- to 1.8-fold), approximately equivalent, increases (rather than decreases) in resistance to doxorubicin, whereas for vincristine no consistent trend was observed. Identical results were also obtained with phorbol-12,13-dibutyrate. These results indicate that PKC activity can be decreased and increased in MDR cells. Both staurosporine inhibition and phorbol ester activation failed to produce changes in drug resistance that would be considered consistent with the resulting degree of PKC activity. Short-term phorbol ester exposure can change the sensitivity of the cells to doxorubicin without changing the relative drug resistance. PKC activity in these cells may then be unrelated to MDR.
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PMID:Protein kinase C activity and multidrug resistance in MOLT-3 human lymphoblastic leukemia cells resistant to trimetrexate. 182 24

A novel gonadotropin-releasing hormone (GnRH) agonist (folligen) which stimulates follicular maturation has been developed in our laboratory. The direct effect of folligen and a well-known superactive GnRH analogue, buserelin, on the MDA-MB-231 human breast cancer cell line was investigated. Folligen was found to be slightly more active in inhibiting cell proliferation than buserelin, and significant differences were found in the signal transduction pathways activated by these analogues. These results demonstrate for the first time that tyrosine kinases and/or phospholipid turnover together with protein kinase C activation can be directly involved in the antitumor activity of GnRH analogues. The results also suggest that folligen and buserelin might have a different mechanism of action on this human breast cancer cell line.
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PMID:Gonadotropin-releasing hormone analogues inhibit cell proliferation and activate signal transduction pathways in MDA-MB-231 human breast cancer cell line. 190 71

We have previously shown that phenothiazines sensitize multidrug resistant (MDR) cells to chemotherapeutic drugs in a manner related to specific structural features, and have identified structurally related thioxanthenes with increased anti-MDR activity. We have now studied the structure-activity relationships of 16 thioxanthenes in the human breast cancer line MCF-7 AdrR. trans-Thioxanthene stereoisomers were 2- to 7-fold more potent than cis-thioxanthenes for antagonizing MDR. The most potent thioxanthenes possessed a halogenated tricyclic ring connected by a 3-carbon alkyl bridge to a piperazinyl or piperadinyl side group. The chemosensitizing effects of the lead compound, trans-flupenthixol, its stereoisomer cis-flupenthixol, its phenothiazine homologue fluphenazine, and the calcium channel blocker verapamil, were further studied in a series of sensitive and MDR cell lines. trans-Flupenthixol caused a greater reversal of cellular resistance to doxorubicin, vinblastine, vincristine, and colchicine in MCF-7 AdrR, KB-V1, and P388/DOX MDR cells than the other chemosensitizers. In particular, trans-flupenthixol was 2- to 3-fold more potent for reversing MDR than equimolar concentrations of verapamil. Furthermore, trans-flupenthixol fully reversed resistance to doxorubicin, vincristine, and colchicine in MDR MCF-7 and NIH 3T3 cells transfected with the mdr1 gene. None of these agents altered MDR in a non-P-glycoprotein expressing MCF-7 cell line selected with mitoxantrone, nor in any of the parental cell lines. The stereoselective antagonism of the flupenthixol isomers on several putative cellular targets was studied to explore the mechanism of their chemosensitizing activity. cis- and trans-flupenthixol were equally active inhibitors of protein kinase C and calmodulin. Both cis- and trans-flupenthixol were also potent inhibitors of [3H]azidopine binding to P-glycoprotein. The apparent lack of clinical toxicity of trans-flupenthixol makes it an attractive drug for possible use in the modulation of tumor resistance in vivo if appropriate tissue concentrations can be achieved.
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PMID:Cellular and biochemical characterization of thioxanthenes for reversal of multidrug resistance in human and murine cell lines. 196 58

The neu proto-oncogene product has been found to exist in two interconvertible forms in G8/DHFR mouse fibroblasts. The 185-kilodalton form (p185) present in growing cells is replaced by a 175-kilodalton form (p175) under conditions of serum starvation. This low molecular weight form accounts almost exclusively for the phosphotyrosine content of the receptor and is associated with increased tyrosine kinase activity. Addition of serum, platelet-derived growth factor or tumor promoter induces conversion of p175 to p185 within minutes, and this increase in molecular weight is associated with phosphorylation of serine and threonine; removal of serum growth factors is followed by replacement of p185 with p175 over several hours. Unlike G8/DHFR cells, the human breast cancer cell line SK-Br-3 expresses a high molecular weight neu/HER2 receptor with unchanged phosphotyrosine content in both serum-starved and serum-stimulated cultures. These findings indicate that activation of the neu proto-oncogene product in G8/DHFR cells may be regulated in part by protein kinase C-mediated receptor transmodulation rather than by ligand availability alone.
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PMID:Modulation of a Mr 175,000 c-neu receptor isoform in G8/DHFR cells by serum starvation. 197 80

This paper reviews our work on the localization of transforming growth factor-alpha (TGF alpha) in normal adult tissues and the regulation of its synthesis and that of its receptor. We detected TGF alpha immunohistochemically in brain neurons and showed the TGF alpha mRNA derived from the human brain stem is virtually identical to the mRNA derived from human renal tumour cells. In cells derived from anterior pituitary glands, another site of TGF alpha expression, TGF alpha secretion and mRNA levels can be regulated by phorbol esters. The expression of the epidermal growth factor (EGF) receptor, which is also the TGF alpha receptor, is also stimulated by phorbol esters. Similar stimulation of receptor and ligand expression in human breast cancer cells was shown in response to phorbol esters and EGF. The ability of ligand to stimulate its own synthesis and that of its receptor suggests the presence of an autocrine positive feedback loop, however we were unable to break this loop in the breast cancer cells by antibodies that blocked the interaction of TGF alpha with the EGF receptor. The ability of EGF to stimulate EGF receptor and TGF alpha expression appears to require protein kinase C, since inhibition of this enzyme blocked the ability of EGF to stimulate these genes. These studies raise the possibility that hormones capable of activating protein kinase C could stimulate EGF receptor and TGF alpha expression.
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PMID:TGF alpha in normal physiology. 210 4

The triphenylethylene antiestrogen trans-tamoxifen is an effective antitumor agent used in the treatment of human breast cancer. While the antiestrogenic activity of trans-tamoxifen clearly plays an important role in its tumoricidal action, some of the biological effects of trans-tamoxifen are independent of estrogen. Therapeutic concentrations of trans-tamoxifen inhibit protein kinase C (PKC) and calmodulin-dependent enzymes. PKC and calmodulin play critical roles in growth regulation, and there is evidence that inhibition of PKC and calmodulin by trans-tamoxifen may contribute to the antitumor activity of the drug in vivo. The geometric isomers cis- and trans-tamoxifen have a number of opposing biological activities that have been attributed to their interactions with the estrogen receptor. Cis-tamoxifen is generally estrogenic, whereas trans-tamoxifen is generally antiestrogenic. In this report, we compared the effects of cis- and trans-tamoxifen on PKC activity and on calmodulin-dependent cAMP phosphodiesterase activity. Cis- and trans-tamoxifen inhibited the Ca2(+)- and phosphatidylserine- (PS-) dependent activity of purified rat brain PKC with indistinguishable potencies, but cis-tamoxifen was somewhat more potent than the trans isomer in the inhibition of the Ca2(+)- and PS-independent activity of PKC. In addition, cis-tamoxifen was the more potent isomer in the inhibition of T lymphocyte activation, an event that entails a PKC-requiring signal transduction pathway. A modest preference for the cis isomer was also observed in the inhibition of a calmodulin-dependent cAMP phosphodiesterase. These results suggest a congruence between triphenylethylene binding sites on PKC and on the activated calmodulin-cAMP phosphodiesterase complex.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Inhibition of protein kinase C and calmodulin by the geometric isomers cis- and trans-tamoxifen. 215 63

Estrogen receptor-positive (MCF7) and -negative (BT20) human breast cancer cell lines, which are frequently used for studies on cancer chemotherapy with triphenylethylene (TPE) anti-estrogens, express at least three protein kinase C subspecies. Two of them are identified as type II PKC having the beta-sequence and type III PKC having the alpha-sequence. The other one shows typical characteristics of PKC which responds to Ca2+, phosphatidylserine and diacylglycerol, but shows kinetic properties subtly different from the previously known PKC subspecies. Immunoblot analysis has shown that this enzyme does not correspond to any of the well defined subspecies with known sequence structures. All of these PKC subspecies are similarly susceptible to the TPE antiestrogens.
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PMID:Protein kinase C subspecies in estrogen receptor-positive and -negative human breast cancer cell lines. 222 28

A cell line (RPh-4) insensitive to the effects of phorbol esters has been isolated from MCF-7 human breast cancer cells. The growth pattern of RPh-4 cells in the presence of 50 ng/mL (80 nM) 12-O-tetradecanoylphorbol 13-acetate (TPA) is similar to that of parental MCF-7 cells in the absence of TPA. While phorbol esters inhibit MCF-7 cell proliferation and increase cell volume and protein content, no such effects are observed in RPh-4 cells. TPA affects MCF-7 but not RPh-4 cell cycle in two ways: a G1 block and a delayed passage through G2 phase. Profound alterations in protein kinase C content and activity are observed in RPh-4 versus MCF-7 cells, i.e. (i) a dramatic decline in the cellular enzyme content; (ii) a loss of the capacity to translocate upon acute TPA stimulation for the remainder enzyme; and (iii) a lack of stimulation by phorbol esters of the endogenous Mr 28,000 substrate. However, these striking changes are only transient and rapidly reverse when RPh-4 cells are subcultured in TPA-free medium, with a 60% and an almost total recovery, respectively, after 15 days and 3 months. By contrast, a much lower rate of reversion is observed in terms of cell growth responsiveness to TPA with a total insensitivity to phorbol ester after 80 days and a 50% inhibition of RPh-4 cell proliferation after 3.5 months. Our data clearly demonstrate an apparent dissociation between the cellular protein kinase C content and the biological responsiveness to phorbol ester in the variant RPh-4 cells. Moreover, they suggest that the Mr 28,000 protein phosphorylation event is not directly related to the cell growth arrest induced by phorbol esters in MCF-7 cells.
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PMID:Dissociation between protein kinase C content and biological responsiveness to phorbol esters in tumor promoter-sensitive (MCF-7) and resistant (RPh-4) cells. 224 15

The phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA) stimulated the phosphorylation of two distinct 27 kDa and 28 kDa proteins, respectively, in bovine vascular endothelial cells and in MCF-7 human breast cancer cells. These protein phosphorylation events were correlated to striking opposite cell growth responses to TPA, i.e., stimulation of vascular endothelial cell proliferation and inhibition of MCF-7 cell growth. Exposure of both vascular endothelial and MCF-7 cells to heat shock induced synthesis of the respective 27 kDa and 28 kDa proteins among a set of common and distinct other proteins as well as an increase in the degree of phosphorylation of the two 27 kDa and 28 kDa proteins. These results suggest that the two protein kinase C substrates very likely belong to the family of low molecular mass stress proteins.
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PMID:The respective 27 kDa and 28 kDa protein kinase C substrates in vascular endothelial and MCF-7 cells are most probably heat shock proteins. 233 22


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