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)

Certain point mutations within the hydrophobic transmembrane domains of class I receptor tyrosine kinases have been associated with oncogenic transformation in vitro and in vivo [Gullick, J., and Srinivasan, R. (1998) Breast Cancer Res. Treat. 52, 43-53]. An important example is the replacement of a single (hydrophobic) valine by (charged) glutamate in the rat protein, Neu, and in the homologous human protein, ErbB-2. It has been suggested that the oncogenic nature of this Val-->Glu substitution may derive from alteration of the transmembrane domain's ability to take part in direct side-to-side associations. In the present work, we examined the basis of this phenomenon by studying transmembrane portions of ErbB-2 in fluid bilayer membranes. An expression system was designed to produce such peptides from the wild-type ErbB-2, and from an identical region of the transforming mutant in which Val(659) is replaced by Glu. All peptides were 50-mers, containing the appropriate transmembrane domain plus contiguous stretches of amino acids from the cytoplasmic and extracellular domains. Deuterium heteronuclear probes were incorporated into alanine side chains (thus, each alanine -CH(3) side chain became -CD(3)). Given the presence of natural alanine residues at positions 648 and 657 within ErbB-2, this approach afforded heteronuclear probes within the motif Ser(656)AlaValValGlu(660), thought to be important for homodimer formation, and nine residues upstream of this site. Further peptides were produced, by site-directed mutagenesis, to confirm spectral assignments and to provide an additional probe location at position 670 (11 residues downstream of the motif region). On SDS-polyacrylamide gels, the transmembrane peptides migrated as predominant monomers in equilibrium with smaller populations of homodimers/-oligomers. CD spectra of both wild-type and transforming mutant peptides were consistent with the transmembrane portions being basically alpha-helical. (2)H NMR spectra of each transmembrane peptide were obtained in fluid phospholipid bilayers of 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) from 35 to 65 degrees C. Results were consistent with the concept that the glutamic acid residue characterizing the mutant is uncharged at neutral pH. Narrowed spectral components from species rotating rapidly and symmetrically within the membrane appeared to represent monomeric peptide. Mutation of Val(659) to Glu within the hydrophobic domain induced changes in side chain angulation of at least 6-8 degrees at Ala(657) (i.e., within the five amino acid motif thought to be involved in homodimer formation), and downstream of this site to residue 670. There was little evidence of effect at the upstream site (Ala(648)) at the membrane surface. This result argues that the transforming mutation is associated with significant intramolecular rearrangement of the monomeric transmembrane helix-extending over some four helix turns-which could influence its lateral associations. In addition, temperature effects on spectral quadrupole splittings suggested that there is greater peptide backbone flexibility for the wild-type transmembrane region.
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PMID:Val(659)-->Glu mutation within the transmembrane domain of ErbB-2: effects measured by (2)H NMR in fluid phospholipid bilayers. 1082 74

BRCA1 encodes a familial breast cancer suppressor that has a critical role in cellular responses to DNA damage. Mouse cells deficient for Brca1 show genetic instability, defective G2-M checkpoint control and reduced homologous recombination. BRCA1 also directly interacts with proteins of the DNA repair machinery and regulates expression of both the p21 and GADD45 genes. However, it remains unclear how DNA damage signals are transmitted to modulate the repair function of BRCA1. Here we show that the BRCA1-associated protein CtIP becomes hyperphosphorylated and dissociated from BRCA1 upon ionizing radiation. This phosphorylation event requires the protein kinase (ATM) that is mutated in the disease ataxia telangiectasia. ATM phosphorylates CtIP at serine residues 664 and 745, and mutation of these sites to alanine abrogates the dissociation of BRCA1 from CtIP, resulting in persistent repression of BRCA1-dependent induction of GADD45 upon ionizing radiation. We conclude that ATM, by phosphorylating CtIP upon ionizing radiation, may modulate BRCA1-mediated regulation of the DNA damage-response GADD45 gene, thus providing a potential link between ATM deficiency and breast cancer.
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PMID:Functional link of BRCA1 and ataxia telangiectasia gene product in DNA damage response. 1091 Mar 65

Matriptase is an epithelial-derived, integral membrane serine protease. The enzyme was initially isolated from human breast cancer cells and has been implicated in breast cancer invasion and metastasis. In the current study, using active matriptase isolated from human milk, we demonstrate that matriptase is able to cleave various synthetic substrates with arginine or lysine as their P1 sites and prefers small side chain amino acids, such as Ala and Gly, at P2 sites. For the most reactive substrates, N-tert-butoxycarbonyl (N-t-Boc)-gamma-benzyl-Glu-Ala-Arg-7-amino-4-methylcoumarin (AMC) and N-t-Boc-Gln-Ala-Arg-AMC, the K(m) values were determined to be 3. 81 and 4.89 microm, respectively. We further demonstrated that matriptase can convert hepatocyte growth factor/scattering factor to its active form, which can induce scatter of Madin-Darby canine kidney epithelial cells and can activate c-Met tyrosine phosphorylation in A549 human lung carcinoma cells. In addition, we noted that matriptase can activate urokinase plasminogen activator but has no affect on plasminogen. These results suggest that matriptase could act as an epithelial, upstream membrane activator to recruit and activate stromal-derived downstream effectors important for extracellular matrix degradation and epithelial migration, two major events of tissue remodeling, cancer invasion, and metastasis.
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PMID:Activation of hepatocyte growth factor and urokinase/plasminogen activator by matriptase, an epithelial membrane serine protease. 1096 9

The screening of a series of arylsulfonylureido derivatives of amines (such as histamine, or dopamine), aliphatic/aromatic amino acids (such as Gly, beta-Ala, Val, Lys, Arg, Phe, Tyr, DOPA, etc.) and dipeptides (such as GlyGly, beta-AlaHis) led to the identification of three derivatives that possess tumor growth inhibitory properties against several leukemia, non-small cell lung, ovarian, melanoma, colon, CNS, renal, and breast cancer cell lines in vitro. The new derivatives were prepared by reaction of 4-toluenesulfonyl isocyanate with (protected) amines, amino acids or dipeptides. The mechanism of antitumor action with these new derivatives is not known at the moment but it may imply uncoupling of mitochondria, as for the structurally related diarylsulfonylurea sulofenur, an investigational anticancer agent.
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PMID:4-toluenesulfonylureido derivatives of amines, amino acids and dipeptides: a novel class of potential antitumor agents. 1103 76

Vitamin D(3) compounds are currently in clinical trials for human breast cancer and offer an alternative approach to anti-hormonal therapies for this disease. 1alpha,25-Dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)), the active form of vitamin D(3), induces apoptosis in breast cancer cells and tumors, but the underlying mechanisms are poorly characterized. In these studies, we focused on the role of caspase activation and mitochondrial disruption in 1alpha,25(OH)(2)D(3)-mediated apoptosis in breast cancer cells (MCF-7) in vitro. The effect of 1alpha,25(OH)(2)D(3) on MCF-7 cells was compared with that of tumor necrosis factor alpha, which induces apoptosis via a caspase-dependent pathway. Our major findings are that 1alpha,25(OH)(2)D(3) induces apoptosis in MCF-7 cells by disruption of mitochondrial function, which is associated with Bax translocation to mitochondria, cytochrome c release, and production of reactive oxygen species. Moreover, we show that Bax translocation and mitochondrial disruption do not occur after 1alpha,25(OH)(2)D(3) treatment of a MCF-7 cell clone selected for resistance to 1alpha,25(OH)(2)D(3)-mediated apoptosis. These mitochondrial effects of 1alpha,25(OH)(2)D(3) do not require caspase activation, since they are not blocked by the cell-permeable caspase inhibitor z-Val-Ala-Asp-fluoromethylketone. Although caspase inhibition blocks 1alpha,25(OH)(2)D(3)-mediated events downstream of mitochondria such as poly(ADP-ribose) polymerase cleavage, external display of phosphatidylserine, and DNA fragmentation, MCF-7 cells still execute apoptosis in the presence of z-Val-Ala-Asp-fluoromethylketone, indicating that the commitment to 1alpha,25(OH)(2)D(3)-mediated cell death is caspase-independent.
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PMID:Role of mitochondria and caspases in vitamin D-mediated apoptosis of MCF-7 breast cancer cells. 1105 35

Tamoxifen (TAM) is widely used in the treatment of breast cancer. The cytostatic effects of TAM have been attributed to the antagonism of estrogen receptor (ER) and inhibition of estrogen-dependent proliferative events. However, the mechanism by which TAM is also effective against certain ER-negative breast tumors remains to be elucidated. Here we report that TAM induced the activity of caspase-3-like proteases in ER-negative breast cancer cell lines MDA-MB-231 and BT-20, as evidenced by the cleavage of fluorogenic tetrapeptide substrate and of poly(ADP-ribose) polymerase. The activation of caspase-3-like proteases preceded TAM-induced chromatin condensation and nuclear fragmentation, the typical apoptotic morphologies. Pretreatment of cells with a specific inhibitor of caspase-3, acetyl-Asp-Glu-Val-Asp-aldehyde, or with a general inhibitor of caspases, benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone, prevented TAM-induced apoptosis. TAM also stimulated c-Jun NH2-terminal kinase (JNK) 1 activity, and interfering with the JNK pathway by over-expressing a DN JNK1 mutant attenuated TAM-induced apoptosis. In addition, treatment of cells with a lipid-soluble antioxidant vitamin E blocked TAM-induced caspase-3 and JNK1 activation as well as apoptosis, whereas water-soluble antioxidants N-acetyl L-cysteine and glutathione had little effect. Thus, this study demonstrates that TAM induces apoptosis in ER-negative breast cancer cells through caspase-3 and JNK1 pathways, which are probably initiated at the cell membrane by an oxidative mechanism.
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PMID:Activation of caspase-3 and c-Jun NH2-terminal kinase-1 signaling pathways in tamoxifen-induced apoptosis of human breast cancer cells. 1108 19

Breast cancer frequently spreads to bone and is almost always associated with osteolysis. This tumor-induced osteolysis is caused by increased osteoclastic bone resorption. Bisphosphonates are used successfully to inhibit bone resorption in tumor bone disease and may prevent development of new osteolytic lesions. The classical view is that bisphosphonates only act on bone cells. We investigated their effects on breast cancer cells using three human cell lines, namely, MCF-7, T47D, and MDA.MB.231, and we tested four structurally different bisphosphonates: clodronate, pamidronate, ibandronate, and zoledronate. We performed time course studies for each bisphosphonate at various concentrations and found that all four compounds induced a nonreversible growth inhibition in both MCF-7 and T47D cell lines in a time- and dose-dependent manner. The MDA.MB.231 cell line was less responsive. Bisphosphonates induced apoptosis in MCF-7 and cell necrosis in T47D cells. The inhibition of MCF-7 cell proliferation could be reverted almost completely by the benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone (z-VAD-fmk) inhibitor of caspases, suggesting that the apoptotic process observed in the MCF-7 cell line is mediated, at least partly, by the caspase system. Caspase activity was little changed by bisphosphonates in T47D cells and the inhibitor of caspase did not modify bisphosphonates effects. In summary, we found that bisphosphonates inhibit breast cancer cell growth by inducing cell death in vitro. Such effects could contribute to the beneficial role of bisphosphonates in the treatment and the prevention of tumor-induced osteolysis.
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PMID:Bisphosphonates induce breast cancer cell death in vitro. 1109 2

The antiestrogen tamoxifen (TAM) is extensively metabolized by cytochrome P-450 in humans and rodents. The active, estrogen receptor-binding metabolites, 4-hydroxy TAM (OHT) and N-desmethyl TAM (DMT) have been well characterized. We showed that the s.c. injection of 1 mg/kg TAM in adult female Sprague Dawley rats bearing carcinogen-induced mammary tumors resulted in rapid serum decline of parent TAM but higher exposure of the metabolites, OHT and DMT. We found for the first time that the administration of TAM for a short time resulted in a delayed induction of caspase activity and apoptosis within the mammary tumors. When TAM, OHT, or DMT was added to human breast cancer cell lines in culture, each elicited a time- and dose-dependent induction of caspase activity, preceding apoptosis. Importantly, pretreatment of the cells with a pharmacological inhibitor of caspases [benzyloxy Val-Ala-Asp-fluoromethyl ketone (z-VAD-fmk)] blocked apoptosis induced by all three of the compounds, implicating a critical role of caspases in TAM-, OHT-, or DMT-induced apoptosis. The results obtained from these studies suggest that one possible mechanism of inhibition of mammary carcinogenesis and tumor growth in vivo may be the induction of caspase-dependent apoptosis, and that the metabolites OHT and DMT may contribute to the antitumor effect of TAM.
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PMID:Pharmacodynamics of tamoxifen and its 4-hydroxy and N-desmethyl metabolites: activation of caspases and induction of apoptosis in rat mammary tumors and in human breast cancer cell lines. 1111 41

We have developed matrix metalloprotease (MMP) inhibitors based on synthetic peptides incorporating a non-cleavable peptide-bond isostere at the site of the putative scissile bond. These inhibitors, N-alpha-phthaloyl-Gly-psi(CO-CH2)-Leu-Tyr-Ala-NH2 (Pht-G-CH2-LYA-NH2) and N-alpha-phthaloyl-Gly-psi(CO-CH2)-Leu-Tic-Ala-NH2 (Pht-G-CH2-LTcA-NH2) were kinetically evaluated against the type IV collagenases, gelatinase A (MMP-2) and B (MMP-9), and compared with an exactly analogous chelating-based inhibitor, N-alpha-mercaptoacetyl-Leu-Tyr-Ala-NH2 (HSCH2CO-LYA-NH2). The peptide inhibitors were also tested for their anti-invasive effects on breast carcinoma cell lines using a modification of the Boyden chamber assay. Gelatin zymography was utilized to identify gelatinolytic activities present in media removed from cultured breast cancer cells. Of the two N-alpha-phthalimidomethyl-ketomethylene peptide-based inhibitors, Pht-G-CH2-LYA-NH2 proved the more effective inhibitor of MMP-2 and MMP-9 (Ki 34.27 and 45.75 microM, respectively). However, when tested against two breast cancer cell lines, T47D and MDA-MB-231, both inhibitors were able to effectively reduce tumour cell invasion through a type IV collagen matrix by up to 91.2%. Of particular interest was the observation that Pht-G-CH2-LYA-NH2 was the most potent inhibitor of invasion by the highly aggressive MDA-MB-231 cells, despite the cells' relative lack of active secreted metalloprotease activity. The results obtained from this kinetic and anti-invasive analysis of the new inhibitors suggest that compounds incorporating the N-alpha-phthalimidomethyl-ketomethylene peptide-bond isostere may have potential for development as new agents with anti-metastatic properties.
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PMID:A study of the anti-invasive properties of N-alpha-phthalimidomethyl-ketomethylene tripeptide-based metalloprotease inhibitors. 1129 48

The family of GH secretagogues (GHS) includes synthetic peptidyl (hexarelin) and nonpeptidyl (MK-0677) molecules possessing specific receptors in the pituitary and central nervous system as well as in peripheral tissues, including the heart and some endocrine organs. A gastric-derived peptide, named ghrelin, has recently been proposed as the natural ligand of the GHS receptors (GHS-Rs). The presence of specific GHS-Rs has now been investigated in nontumoral and neoplastic human breast tissue using a radioiodinated peptidyl GHS ([(125)I]-Tyr-Ala-hexarelin) as ligand. Specific binding sites for GHS were detected in membranes from several types of breast carcinomas, whereas a negligible binding was found in fibroadenomas and mammary parenchyma. The highest binding activity was found in well-differentiated (G1) invasive breast carcinomas and was progressively reduced in moderately (G2) to poorly (G3) differentiated tumors. [(125)I]-Tyr-Ala-hexarelin bound to tumor membranes was displaced by different unlabeled GHS such as hexarelin, Tyr-Ala-hexarelin, human ghrelin, and MK-0677 as well as by desoctanoyl-ghrelin and hexarelin derivative EP-80317, which are devoid of GH-releasing properties in vivo. In contrast, no competition was seen between radiolabeled Tyr-Ala-hexarelin and some peptides (CRF and insulin-like growth factor I) structurally and functionally unrelated to hexarelin or when GHRH and SRIF were tested in the displacement studies. The presence of specific GHS binding sites was also demonstrated in three different human breast carcinoma cell lines (MCF7, T47D, and MDA-MB231), in which, surprisingly, no messenger RNA for GHS-R1a was demonstrated by RT-PCR. In these cell lines, ghrelin (as well as hexarelin, MK-0677, EP-80317, and even desoctanoyl ghrelin) caused a significant inhibition of cell proliferation at concentrations close to their binding affinity. In conclusion, this study provides the first demonstration of specific GHS binding sites, other than GHS-R1, in breast cancer. These receptors probably mediate growth inhibitory effects on breast carcinoma cells in vitro.
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PMID:Identification, characterization, and biological activity of specific receptors for natural (ghrelin) and synthetic growth hormone secretagogues and analogs in human breast carcinomas and cell lines. 1129 11


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