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1.
Br J Cancer ; 92(2): 389-95, 2005 Jan 31.
Article in English | MEDLINE | ID: mdl-15558069

ABSTRACT

Recent studies have suggested that aneuploidy in malignant tumours could be a consequence of centrosome aberrations. Using immunofluorescence analysis with an antibody against gamma-tubulin and DNA image cytometry, we measured centrosome aberrations and DNA ploidy patterns in fine-needle aspiration biopsies (FNABs) of 58 breast lesions. Benign lesions did not show any centrosome aberrations. DNA diploid carcinomas showed a mean percentage of cells with centrosomal defects of 2.1%. The aneuploid invasive carcinomas could be divided into two subgroups by their significantly (P=0.0003) different percentage of cells with centrosome aberrations (2.0 and 10.3%, respectively) and their significantly (P=0.0003) different percentage of cells with nonmodal DNA content values determined by the Stemline Scatter Index (SSI), a measure of genomic instability. The percentage of cells with centrosome aberrations demonstrated a positive, linear correlation with the corresponding SSI (r=0.82, P<0.0001) and loss of tissue differentiation (r=0.78, P<0.0001). Our results indicate the percentage of cells with centrosome aberrations as being sufficient to divide the investigated tumours into three significantly different groups: benign lesions with no centrosomal aberrations, and two malignant tumour types with mean values of 2.1 and 9.6% of centrosomal defects, respectively. Together, these results demonstrate that centrosome aberrations correlate with genomic instability and loss of tissue differentiation. Furthermore, this study shows the feasibility of centrosomal analysis in FNAB of the breast and suggests centrosomal aberrations as possessing diagnostic and prognostic value.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Centrosome/pathology , DNA, Neoplasm/analysis , Genomic Instability , Adult , Aged , Aged, 80 and over , Aneuploidy , Biopsy, Fine-Needle , Breast Neoplasms/classification , Fluorescent Antibody Technique , Humans , Image Processing, Computer-Assisted , Middle Aged
2.
Anticancer Res ; 21(1B): 509-12, 2001.
Article in English | MEDLINE | ID: mdl-11299796

ABSTRACT

Squamous epithelial cancer in situ (CIS) of the upper aerodigestive tract is a histopathologically well-defined condition. There is yet no reliable way to predict whether a CIS lesion will progress to invasive cancer, remain stable or regress. In the search for markers able to foretell clinical outcome, we performed immunohistochemical staining with a polyclonal antibody against recombinant gamma 2 chain of laminin-5 in 33 laryngeal CIS lesions. All six CIS lesions which progressed to invasive cancer, within a follow-up time of 5 years, were laminin-5 positive (100%), whereas only 10 out of 27 lesions which did not progress were positive (37%) (p < 0.01). Our data showed that a positive laminin-5 laryngeal CIS lesion indicates a high risk for progression to invasive cancer.


Subject(s)
Biomarkers, Tumor/analysis , Carcinoma in Situ/pathology , Carcinoma, Squamous Cell/pathology , Cell Adhesion Molecules/analysis , Laryngeal Neoplasms/pathology , Neoplasm Invasiveness/diagnosis , Neoplasm Proteins/analysis , Adult , Aged , Animals , Carcinoma in Situ/chemistry , Carcinoma, Squamous Cell/chemistry , Case Management , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/immunology , Disease Progression , Female , Follow-Up Studies , Humans , Immunoenzyme Techniques , Laryngeal Neoplasms/chemistry , Male , Middle Aged , Neoplasm Proteins/immunology , Prognosis , Protein Subunits , Rabbits , Recombinant Fusion Proteins/immunology , Risk , Kalinin
3.
Cell Mol Life Sci ; 55(3): 467-71, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10228560

ABSTRACT

Signalling via the protein kinase Raf-MEK-ERK pathway is of major importance for transformation by oncogenes. To identify genes affected by inhibition of this pathway, c-JUN transformed rat fibroblasts were treated with a MEK1 inhibitor (PD98059) and subjected to two-dimensional gel electrophoresis after cell lysis. Gene products with expression influenced by MEK1 inhibition were determined by mass spectrometry of fragments from in-gel tryptic digestions. The expression of pirin, a nuclear factor I-interacting protein, was lowered after inhibition of MEK1. Western blot analysis revealed increased expression of pirin in RAS and c-JUN transformed cells in the absence of PD98059. Inhibition of MEK1 also led to reduced expression of alpha-enolase, phosphoglycerate kinase, elongation factor 2 and heterogeneous nuclear ribonucleoprotein A3, the latter two being detected as truncated proteins. In contrast, the level of ornithine aminotransferase was increased. We conclude that inhibition of MEK1 results in major alterations of protein expression in c-JUN transformed cells, suggesting that this pathway is important for oncogene-induced phenotypic changes.


Subject(s)
Carrier Proteins/biosynthesis , Cell Transformation, Neoplastic/genetics , Fibroblasts/metabolism , Genes, jun , Genes, ras , Mitogen-Activated Protein Kinase Kinases , Mitogen-Activated Protein Kinases , Nuclear Proteins/biosynthesis , Protein Serine-Threonine Kinases/physiology , Protein-Tyrosine Kinases/physiology , Signal Transduction/genetics , Animals , Calcium-Calmodulin-Dependent Protein Kinases/physiology , Carrier Proteins/genetics , Cell Line, Transformed , Dioxygenases , Fibroblasts/drug effects , Flavonoids/pharmacology , Heterogeneous-Nuclear Ribonucleoproteins , MAP Kinase Kinase 1 , Mass Spectrometry , Mitogen-Activated Protein Kinase 1 , Mitogen-Activated Protein Kinase 3 , Nuclear Proteins/genetics , Ornithine-Oxo-Acid Transaminase/biosynthesis , Ornithine-Oxo-Acid Transaminase/genetics , Peptide Elongation Factor 2 , Peptide Elongation Factors/biosynthesis , Peptide Elongation Factors/genetics , Phosphoglycerate Kinase/biosynthesis , Phosphoglycerate Kinase/genetics , Phosphopyruvate Hydratase/biosynthesis , Phosphopyruvate Hydratase/genetics , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins c-raf/physiology , Rats , Ribonucleoproteins/biosynthesis , Ribonucleoproteins/genetics , Transfection
4.
Clin Exp Metastasis ; 17(8): 649-54, 1999.
Article in English | MEDLINE | ID: mdl-10919709

ABSTRACT

Increased urokinase plasminogen activator (u-PA) production is associated with tumor invasion and metastasis in several malignancies, including breast cancer. The mechanisms underlying constitutive u-PA expression are not well understood. We examined the relationship between the signal strength of the ERK pathway and the level of u-PA expression in the metastatic human breast cancer cell line MDA-MB-231. Treatment with the MEK1 inhibitor PD98059 resulted in decreased ERK1/2 phosphorylation and decreased u-PA mRNA and protein expression. Inhibition of ERK1/2 activity also led to decreased cell proliferation and to decreased cyclin D1 expression. Less than 5% of total ERK1/2 was phosphorylated in exponentially growing MDA-MB-231 cells, and ERK1/2 activity could be stimulated by okadaic acid. Okadaic acid did not stimulate u-PA expression, but induced strong expression of the cdk-inhibitor p21Cip1. These findings suggest that ERK1/2 signaling is tuned to a level which results in high u-PA expression and rapid cell proliferation.


Subject(s)
Breast Neoplasms/enzymology , Breast Neoplasms/pathology , MAP Kinase Kinase Kinase 1 , MAP Kinase Signaling System/physiology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinases/metabolism , Urokinase-Type Plasminogen Activator/biosynthesis , Breast Neoplasms/secondary , Cell Division/physiology , Cyclin D1/biosynthesis , Cyclin D1/genetics , Cyclin-Dependent Kinase Inhibitor p21 , Cyclins/biosynthesis , Cyclins/genetics , Enzyme Inhibitors/pharmacology , Flavonoids/pharmacology , Gene Expression Regulation, Neoplastic , Humans , Mitogen-Activated Protein Kinase 1/physiology , Mitogen-Activated Protein Kinase 3 , Mitogen-Activated Protein Kinases/physiology , Neoplasm Metastasis , Okadaic Acid/pharmacology , Phosphorylation/drug effects , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Protein Serine-Threonine Kinases/physiology , Proto-Oncogene Proteins c-jun/biosynthesis , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-raf/metabolism , Proto-Oncogene Proteins c-raf/physiology , Tumor Cells, Cultured
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