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

Changes in the CD44 variant (CD44v) isoforms on the cell surface have been correlated with tumor metastasis. In this study we have examined the expression of CD44 variant isoforms in human breast carcinoma samples by a variety of techniques including immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and nucleotide sequencing. Using RT-PCR, we have determined that normal human breast tissue contains primarily the CD44 epithelial (CD44E) form and very little CD44 standard (CD44s) form. However, metastatic breast carcinomas appear to overexpress both the CD44E and CD44s forms and also display multiple new species of CD44 variant isoforms. Histocytochemical staining using anti-CD44 antibody (recognizing a common determinant of the CD44 class of glycoproteins) confirms that the CD44 molecules are overexpressed and preferentially located in metastatic breast cancer tissues. Nucleotide sequencing analyses indicate that at least four new CD44 variant isoforms (i.e., displaying unique splicing via the insertion or the deletion of exons 7, 10, 11, and 14) may be closely associated with human metastatic breast cancers. These newly described CD44 variant isoforms may be useful for monitoring the progression of human breast cancer metastasis.
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PMID:New CD44 splice variants associated with human breast cancers. 752 35

The relevant anti-tumour mechanisms of recombinant interleukin-2 (rIL-2) in vivo are unclear but an influx of T-lymphocytes and macrophages has been noted in regressing lesions. One of the dose limiting toxicities of rIL-2 is the development of a capillary leak syndrome attributed to widespread endothelial activation. Changes in expression of endothelial and leucocyte-associated adhesion molecules were assessed in tumour and uninvolved skin in patients with metastatic breast cancer receiving rIL-2. Increased expression of intracellular adhesion molecule-1, its leucocyte-associated ligand, leucocyte function associated molecule-1, vascular cell adhesion molecule and its ligand, very late after activation antigen-4 as well as members of the selectin family of adhesion molecules, were noted in uninvolved skin following rIL-2. Expression of these adhesion molecules was noted in tumour stroma before rIL-2 but little change was observed following rIL-2 infusion. An influx of monocytes and T-lymphocytes (expressing the IL-2 receptor and of the memory subtype) and a lower number of neutrophils was noted in uninvolved skin following rIL-2. Although monocytes and T-lymphocytes were present in tumour stroma before rIL-2 no changes were observed following infusion. The changes noted in the dermis contrast with those seen at tumour sites and may partly explain the low therapeutic index of rIL-2.
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PMID:Adhesion molecule expression and leucocyte trafficking following immunotherapy with recombinant interleukin-2. 873 38

Concentrations of soluble CD44 standard (sCD44std) and CD44 variant 6 (sCD44v6) isoforms were determined in the sera of 59 patients with distant metastasis from breast cancer receiving second line hormone- or chemotherapy, in comparison to 46 breast cancer patients without detectable recurrent disease and 21 healthy blood donors. The sera of non-metastatic breast cancer, patients contained sCD44std and sCD44v6 concentrations similiar to those of healthy blood donors. In sera of patients with distant metastasis from recurrent breast cancer the median values of sCD44std and sCD44v6 were significantly higher (sCD44std: 502 ng/ml, p=0.03; sCD44v6: 193 ng/ml, p = 0.002) in comparison to healthy blood donors and patients with non-metastatic disease (p<0.001 for both parameters). A significant correlation was observed between sCD44v6 serum concentrations and the number of metastasized organs (p=0.0018), serum LDH concentrations (p<0.0001), tumor grading (p=0.025) and the presence of hepatic metastasis (p=0.028). Furthermore, sCD44v6 expression was associated with the patient's responsiveness to second line hormone- or chemotherapy. Non-responders had significantly higher sCD44v6 levels compared with the responder group (median: 447 ng/ml vs 171 ng/ml; p=0.0007). Logistic regression analysis indicated that sCD44v6 serum levels above 250 ng/ml (p =0.033) and the presence of hepatic metastasis (p=0.009) were independent factors predicting an unfavourable response to therapy.
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PMID:Predictive relevance of soluble CD44v6 serum levels for the responsiveness to second line hormone- or chemotherapy in patients with metastatic breast cancer. 1171

Targeting drugs to receptors involved in tumor angiogenesis is a novel and promising approach to improve cancer treatment. In this study, we evaluated the antitumor activity of paclitaxel (PTX) conjugated with a bicyclic peptide E[c(RGDyK)](2) (RGD) in a metastatic breast cancer cell line (MDA-MB-435). The cyclic RGD peptide selectively binds to alpha(v) integrin receptors that are highly expressed in metastatic cancer cells. PTX, an antimicrotubule agent, is a potent antitumor agent commonly used in the treatment of advanced metastatic breast cancer. The in vitro results showed that RGD peptide inhibited cell cycle proliferation by arresting cells in G(0)/G(1)-phase. The PTX-RGD conjugate inhibited cell proliferation with activity comparable to that observed for paclitaxel, both of which were mediated by an arrest of G(2)/M-phase of the cell cycle followed by apoptosis. Although the PTX-RGD conjugate showed slightly decreased integrin binding affinity than the unconjugated peptide, it indicated integrin specific accumulation in vivo. (125)I-Labeled PTX-RGD showed highest tumor uptake at 2 h postinjection (2.72 +/-0.16%ID/g) and best tumor/background contrast after 4 h postinjection. Our results demonstrate the potential of tumor-targeted delivery of paclitaxel based on the specific recognition of cell adhesion molecule alpha(v)beta(3) integrin to reduce toxicity and enhance selective killing of cancer cells.
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PMID:Synthesis and biological evaluation of dimeric RGD peptide-paclitaxel conjugate as a model for integrin-targeted drug delivery. 1571 77

Voltage-gated Na(+) channels (VGSCs), predominantly the 'neonatal' splice form of Na(v)1.5 (nNa(v)1.5), are upregulated in metastatic breast cancer (BCa) and potentiate metastatic cell behaviours. VGSCs comprise one pore-forming alpha subunit and one or more beta subunits. The latter modulate VGSC expression and gating, and can function as cell adhesion molecules of the immunoglobulin superfamily. The aims of this study were (1) to determine which beta subunits were expressed in weakly metastatic MCF-7 and strongly metastatic MDA-MB-231 human BCa cells, and (2) to investigate the possible role of beta subunits in adhesion and migration. In both cell lines, the beta subunit mRNA expression profile was SCN1B (encoding beta1)>>SCN4B (encoding beta4)>SCN2B (encoding beta2); SCN3B (encoding beta3) was not detected. MCF-7 cells had much higher levels of all beta subunit mRNAs than MDA-MB-231 cells, and beta1 mRNA was the most abundant. Similarly, beta1 protein was strongly expressed in MCF-7 and barely detectable in MDA-MB-231 cells. In MCF-7 cells transfected with siRNA targeting beta1, adhesion was reduced by 35%, while migration was increased by 121%. The increase in migration was reversed by tetrodotoxin (TTX). In addition, levels of nNa(v)1.5 mRNA and protein were increased following beta1 down-regulation. Stable expression of beta1 in MDA-MB-231 cells increased functional VGSC activity, process length and adhesion, and reduced lateral motility and proliferation. We conclude that beta1 is a novel cell adhesion molecule in BCa cells and can control VGSC (nNa(v)1.5) expression and, concomitantly, cellular migration.
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PMID:A novel adhesion molecule in human breast cancer cells: voltage-gated Na+ channel beta1 subunit. 1904 53

Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a cell-cell adhesion molecule, has been revealed to perform an important role in tumor progression. Although there are a number of studies on CEACAM1 in patients with breast cancer, there is limited information on the roles of CEACAM1 in breast cancer metastasis. The present study aimed to identify whether CEACAM1 is involved in breast cancer development and to investigate the underlying mechanisms. First, the expression of CEACAM1 was observed in patients with breast cancer, and the association between CEACAM1 expression levels and migration and invasion of breast cancer cells was analyzed. As there are 12 isoforms of CEACAM1, of which CEACAM1-4S dominates in the human breast epithelium, subsequent study focused on CEACAM1-4S as a representative of all the isoforms. Results of the present study demonstrated that CEACAM1-4S suppresses breast cancer cell invasion and migration in a manner that is dependent on the balance between matrix metalloproteinase 2/tissue inhibitor of metalloproteinase 2 and E-/N-cadherin expression. In addition, CEACAM1-4S was likely to cause reversal of epithelial-mesenchymal transition of breast cancer cells through repressing Smad2 and signal transducer and phosphorylation of activator of transcription 3. In conclusion, the present study demonstrated that CEACAM1-4S performs an inhibitory role in breast cancer metastasis, and restoring CEACAM1-4S expression may provide a novel strategy for therapy of patients with metastatic breast cancer.
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PMID:Inhibition of cell invasion and migration by CEACAM1-4S in breast cancer. 2908 77