Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 9 de 9
Filter
1.
Oncogene ; 35(35): 4601-10, 2016 09 01.
Article in English | MEDLINE | ID: mdl-26820992

ABSTRACT

Almost half of all hereditary breast cancers (BCs) are associated with germ-line mutations in homologous recombination (HR) genes. However, the tumor phenotypes associated with different HR genes vary, making it difficult to define the role of HR in BC predisposition. To distinguish between HR-dependent and -independent features of BCs, we generated a mouse model in which an essential HR gene, Rad51c, is knocked-out specifically in epidermal tissues. Rad51c is one of the key mediators of HR and a well-known BC predisposition gene. Here, we demonstrate that deletion of Rad51c invariably requires inactivation of the Trp53 tumor suppressor (TP53 in humans) to produce mammary carcinomas in 63% of female mice. Nonetheless, loss of Rad51c shortens the latency of Trp53-deficient mouse tumors from 11 to 6 months. Remarkably, the histopathological features of Rad51c-deficient mammary carcinomas, such as expression of hormone receptors and luminal epithelial markers, faithfully recapitulate the histopathology of human RAD51C-mutated BCs. Similar to other BC models, Rad51c/p53 double-mutant mouse mammary tumors also reveal a propensity for genomic instability, but lack the focal amplification of the Met locus or distinct mutational signatures reported for other HR genes. Using the human mammary epithelial cell line MCF10A, we show that deletion of TP53 can rescue RAD51C-deficient cells from radiation-induced cellular senescence, whereas it exacerbates their centrosome amplification and nuclear abnormalities. Altogether, our data indicate that a trend for genomic instability and inactivation of Trp53 are common features of HR-mediated BCs, whereas histopathology and somatic mutation patterns are specific for different HR genes.


Subject(s)
Breast Neoplasms/genetics , Mammary Neoplasms, Animal/genetics , Rad51 Recombinase/genetics , Tumor Suppressor Protein p53/genetics , Animals , Breast Neoplasms/pathology , DNA-Binding Proteins , Disease Models, Animal , Female , Gene Deletion , Germ-Line Mutation/genetics , Homologous Recombination/genetics , Humans , Mammary Neoplasms, Animal/pathology , Mice , Mice, Knockout
2.
Br J Cancer ; 105(7): 989-95, 2011 Sep 27.
Article in English | MEDLINE | ID: mdl-21897396

ABSTRACT

BACKGROUND: Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein expressed in several solid cancers. Our purpose was to study its role in serous ovarian cancer patients, and the association to clinicopathological variables and molecular markers. METHODS: We collected retrospectively 562 consecutive serous ovarian cancer patients treated at the Helsinki University Central Hospital. We stained tumour tissue microarrays for CIP2A by immunohistochemistry and constructed survival curves according to the Kaplan-Meier method. Associations to clinicopathological and molecular markers were assessed by the χ(2)-test. RESULTS: We found strong cytoplasmic CIP2A immunoreactivity in 212 (40.4%) specimens, weak positivity in 222 (42.4%) specimens, and negative in 90 (17.2%). Immunopositive CIP2A expression was associated with high grade (P<0.0001), advanced stage (P=0.0005), and aneuploidy (P=0.001, χ(2)-test). Cancerous inhibitor of protein phosphatase 2A overexpression was also associated with EGFR protein expression (P=0.006) and EGFR amplification (P=0.043). Strong cytoplasmic CIP2A immunopositivity predicted poor outcome in ovarian cancer patients (P<0.0001, log-rank test). CONCLUSION: Our results show that CIP2A associates with reduced survival and parameters associated with high grade in ovarian cancer patients, and may thus be one of the factors that identify aggressive subtype (type II) of this disease.


Subject(s)
Autoantigens/metabolism , Biomarkers, Tumor/metabolism , Cystadenocarcinoma, Serous/metabolism , Membrane Proteins/metabolism , Ovarian Neoplasms/metabolism , Cohort Studies , Cytoplasm/metabolism , ErbB Receptors/metabolism , Female , Humans , Immunoblotting , Immunoenzyme Techniques , Intracellular Signaling Peptides and Proteins , Middle Aged , Prognosis , Retrospective Studies , Survival Rate , Tissue Array Analysis
3.
Lung Cancer ; 57(3): 317-21, 2007 Sep.
Article in English | MEDLINE | ID: mdl-17485134

ABSTRACT

Tumor hypoxia is generally considered to be related to aggressive behaviour of a tumor. As in lung cancer direct determination of oxygenation is difficult, hypoxia-related proteins have been studied. A number of studies on these proteins show different results and the usefulness of these protein expressions remains questionable. In this article, we relate one of these hypoxia-related proteins (hypoxia-inducible factor, HIF1a) to a direct in vivo spectroscopic measurement of tumor blood saturation performed during bronchoscopy. Seventeen samples from malignancies and non-malignant tissues were studied. Microvascular saturation levels in the no malignancy group equalled 87+/-11.5% (range 71-100%) and in the malignant group 43+/-21% (range 6-63%). This difference was statistically significant (p<0.0002). There was a significant difference in the spectroscopically determined saturations between the biopsies with negative expression of HIF1a and the biopsies with positive expression of HIF1a (p<0.005). From these data, it can be concluded that HIF1a expression is related to a low microvascular blood saturation as determined in vivo by optical spectroscopy. This study may lead to a better acceptance of the usage of different techniques to establish hypoxia in order to study the effect of hypoxia on therapeutic interventions and prognosis of lung cancer.


Subject(s)
Bronchi/metabolism , Hypoxia-Inducible Factor 1, alpha Subunit/metabolism , Hypoxia/metabolism , Lung Neoplasms/blood supply , Adult , Biopsy , Bronchi/pathology , Capillaries , Female , Humans , Hypoxia-Inducible Factor 1, alpha Subunit/analysis , Lung Neoplasms/pathology , Male , Spectrum Analysis/methods
4.
Eur Respir J ; 27(6): 1086-95, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16540497

ABSTRACT

Malignant mesothelioma is a cancer with dismal prognosis. The objective of the present study was to address the role of the immune system, tumour micro-environment and potential immunosuppression in mesothelioma. Expression profiles of 80 cytokines were determined in the supernatant of mesothelioma cell lines and the original patient's pleural effusion. Influx of immune effector cells was detected by immunohistochemistry. Angiogenin, vascular endothelial growth factor, transforming growth factor-beta, epithelial neutrophil-activating protein-78 and several other proteins involved in immune suppression, angiogenesis and plasma extravasation could be detected in both supernatant and pleural effusion. Surrounding stroma and/or infiltrating cells were the most likely source of hepatocyte growth factor, macrophage inflammatory protein (MIP)-1delta, MIP-3alpha, neutrophil-activating peptide-2, and pulmonary and activation-regulated chemokine that can cause leukocyte infiltration and activation. There was a massive influx of CD4+ and CD8+ T-lymphocytes and macrophages, but not of dendritic cells, in human mesothelioma biopsies. It was further demonstrated that human mesothelioma tissue contained significant amounts of Foxp3+CD4+CD25+ regulatory T-cells. When these CD25+ regulatory T-cells were depleted in an in vivo mouse model, survival increased. Mesothelioma is infiltrated by immune effector cells but also contains cytokines and regulatory T-cells that suppress an efficient immune response. Immunotherapy of mesothelioma might be more effective when combined with drugs that eliminate or control regulatory T-cells.


Subject(s)
Cytokines/blood , Immune Tolerance/immunology , Mesothelioma/immunology , Pleural Neoplasms/immunology , T-Lymphocytes, Regulatory/immunology , Aged , Aged, 80 and over , Animals , CD4 Antigens/blood , CD4-CD8 Ratio , Cell Line, Tumor , Female , Forkhead Transcription Factors/blood , Humans , Immunoenzyme Techniques , Immunotherapy , Lymphocyte Depletion , Macrophages/immunology , Male , Mesothelioma/pathology , Mice , Mice, Inbred BALB C , Neoplasm Transplantation/immunology , Pleural Effusion, Malignant/immunology , Pleural Neoplasms/pathology , Proteomics , Receptors, Interleukin-2/blood
5.
Epilepsia ; 34(1): 151-2, 1993.
Article in English | MEDLINE | ID: mdl-8422848

ABSTRACT

A 16-year-old boy with epilepsy developed hypertrophy of the submandibular salivary glands, with high phenytoin (PHT) serum levels. The submandibular salivary glands became normal in 12 days after discontinuation of PHT. Other causes of salivary gland hypertrophy were excluded and we suggest that the hypertrophy was due to PHT.


Subject(s)
Epilepsy, Complex Partial/drug therapy , Phenytoin/adverse effects , Salivary Gland Diseases/chemically induced , Submandibular Gland/pathology , Adolescent , Humans , Hypertrophy/pathology , Male
6.
Clin Chim Acta ; 189(3): 327-34, 1990 Aug 31.
Article in English | MEDLINE | ID: mdl-2225463

ABSTRACT

Patients with 3-hydroxy-3-methylglutaric aciduria due to a deficiency of 3-hydroxy-3-methylglutaryl Coenzyme A lyase usually present with a life-threatening crisis of hypoglycemia, metabolic acidosis and hyperammonemia. Diagnosis of this inborn error of leucine degradation is usually based upon gas-chromatographic analysis of organic acids in a patient's urine. In this paper we describe a simple spectrophotometric method allowing the activity of HMG-CoA lyase to be measured in leukocytes or platelets within a few hours, thus contributing to a rapid, unequivocal diagnosis and subsequent treatment. The validity of the method was established by demonstrating a deficient activity of HMG-CoA lyase in two patients with 3-hydroxy-3-methylglutaric aciduria. Furthermore, using this method, heterozygote detection can be done with great reliability.


Subject(s)
Blood Platelets/enzymology , Leukocytes/enzymology , Oxo-Acid-Lyases/deficiency , Child, Preschool , Female , Humans , Hydrogen-Ion Concentration , Infant , Infant, Newborn , Male , Metabolism, Inborn Errors/blood , Metabolism, Inborn Errors/diagnosis , Oxo-Acid-Lyases/blood , Spectrophotometry/methods
7.
Am J Med Genet ; 14(1): 115-23, 1983 Jan.
Article in English | MEDLINE | ID: mdl-6829599

ABSTRACT

We describe two unrelated malformed infants who died shortly after birth and who had multiple congenital anomalies including hydrops and ascites, facial abnormalities (with median cleft of the upper lip), narrow thorax, protuberant abdomen, and short, bowed limbs. Postmortem radiographs showed very short ribs and disproportionately short long tubular bones; no metaphyseal abnormalities were present. Comparison with earlier described short-rib/short-rib-polydactyly syndromes suggest that the disorder present in our two cases is a new type of short-rib syndrome. One of our patients was born to a consanguineous couple; in a subsequent pregnancy, real-time ultrasonography in the second trimester showed that the female fetus had the same abnormalities as its sib. Diagnosis was confirmed after elective abortion. This suggests that this short-rib syndrome may be an autosomal recessive disorder.


Subject(s)
Abnormalities, Multiple/genetics , Bone Diseases, Developmental/genetics , Ribs/abnormalities , Consanguinity , Face/abnormalities , Female , Genes, Recessive , Humans , Infant, Newborn , Male , Syndrome
SELECTION OF CITATIONS
SEARCH DETAIL
...