Východisko. Zvýšená tvorba onkogenních proteinů je u některých nádorů podmíněná genovou amplifikací. Vztah exprese regulačního proteinu buněčného cyklu, cyklinu D1 a amplifikace genu CCND1 kódujícího tento protein není u invazivních duktálních karcinomů mléčné žlázy (IDC) plně objasněn. Zvýšený zájem vyvolávají vztahy k expresi receptoru pro estrogen (ER). Metody a výsledky. Vyšetřili jsme počet

Background. Overexpression of oncogenic proteins may be caused by gene amplifications. Cyclin D1 participates in regulation of the cell cycle. Relations between cyclin D1 expression and amplification of CCND1 gene encoding this protein in invasive duct breast carcinomas (IDC) are not fully elucidated. An increased interest is also focused on relations to the estrogen receptor (ER). Methods and Re

• MeSH
• amplifikace genu MeSH
• cyklin D1 MeSH
• duktální karcinom genetika   MeSH
• hybridizace in situ fluorescenční MeSH
• lidé MeSH
• nádory prsu genetika   patologie   MeSH
• prognóza MeSH
• receptory pro estrogeny MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH

Breast cancer associated with BRCA1 and BRCA2 gene mutations differs from non-BRCA tumors in several respects. We determined whether there was any difference in CCND1 (11q13) and ZNF217 (20q13) gene amplification with respect to BRCA status. Of 40 breast cancer samples examined, 15 and 9 were from BRCA1 and BRCA2 mutation carriers, respectively, and 16 from patients without mutation. Fluorescence in situ hybridization showed that eight tumors exhibited CCND1 amplification (20%; 3 BRCA1, 3 BRCA2, 2 non-BRCA). ZNF217 amplification was observed in three of 38 cases (8%; 2 BRCA1, 1 non-BRCA). There was no significant difference in CCND1 and ZNF217 amplification between BRCA1, BRCA2 and non-BRCA tumors. CCND1 amplification was associated with decreased disease-free (P = 0.045) and overall survival (P = 0.015). BRCA1 tumors with CCND1 amplification were estrogen receptor negative, in contrast to CCND1 amplified BRCA2 and non-BRCA tumors, suggesting that concurrent CCND1 amplification and estrogen and progesterone receptor negativity may predict germline BRCA1 gene mutation. All ZNF217 amplified tumors were of the medullary histological type (P = 0.002). There was no statistical correlation between CCND1 and ZNF217 amplification and estrogen receptor, progesterone receptor, and ERBB2 expression and TNM classification. CCND1 amplification did not correlate with EGFR expression.

• MeSH
• amplifikace genu MeSH
• cyklin D1 genetika   MeSH
• dospělí MeSH
• duktální karcinom prsu genetika   metabolismus   patologie   MeSH
• erbB receptory metabolismus   MeSH
• genetická predispozice k nemoci MeSH
• hybridizace in situ fluorescenční MeSH
• imunoenzymatické techniky MeSH
• lidé středního věku MeSH
• lidé MeSH
• lobulární karcinom genetika   metabolismus   patologie   MeSH
• mladý dospělý MeSH
• mucinózní adenokarcinom genetika   metabolismus   patologie   MeSH
• nádory prsu genetika   metabolismus   patologie   MeSH
• prognóza MeSH
• protein BRCA1 genetika   MeSH
• protein BRCA2 genetika   MeSH
• proteiny regulující apoptózu MeSH
• receptor erbB-2 metabolismus   MeSH
• receptory pro estrogeny metabolismus   MeSH
• receptory progesteronu metabolismus   MeSH
• trans-aktivátory genetika   MeSH
• zárodečné mutace genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Cyclin D1 is a cell-cycle regulator essential for G1 phase progression and a candidate proto-oncogene implicated in pathogenesis of several human tumour types, including breast carcinomas. In spite of the accumulating genetic evidence, however, there are no data regarding abundance and properties of the cyclin D1 protein in breast cancer. We now report aberrant nuclear overexpression/accumulation of the cyclin D1 protein in about half of the 170 primary breast carcinoma specimens analyzed by monoclonal antibody immunohistochemistry, indicating that the frequency of cyclin D1 abnormalities may be considerably higher than previously deduced from DNA amplification studies. A comparison of the expression patterns in matched lesions at different stages of tumour progression revealed that the cyclin D1 protein aberration appears to reflect a relatively early event and that, when acquired by a tumour, it is maintained throughout breast cancer progression including metastatic spread. In both tumour tissues and breast cancer cell lines, the abundance of this protein shows characteristic variations consistent with a cell-cycle oscillation and the peak levels expressed in G1. In all 7 cell lines whose retinoblastoma (Rb) protein is mutant or complexed to SV40 T antigen, exceptionally low levels of cyclin D1 protein and mRNA were found. Antibody-mediated and anti-sense oligonucleotide knockout experiments demonstrate the requirement for the cell-cycle regulatory function of cyclin D1 in breast cancer lines with single or multiple copies of the gene and reveal the absence of such a requirement in the cell lines with Rb defects. Our data are consistent with the notion that the emerging "Rb-cyclin D1 pathway" represents a frequent target of oncogenic abnormalities in breast cancer.

• MeSH
• buněčný cyklus MeSH
• cyklin D1 MeSH
• cykliny analýza   fyziologie   MeSH
• geny retinoblastomu MeSH
• lidé MeSH
• messenger RNA analýza   MeSH
• molekulární sekvence - údaje MeSH
• nádory prsu * genetika   chemie   patologie   MeSH
• onkogenní proteiny analýza   fyziologie   MeSH
• prsy * chemie   patologie   MeSH
• RNA nádorová analýza   MeSH
• sekvence nukleotidů MeSH
• staging nádorů MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• práce podpořená grantem MeSH

Among the key cell cycle regulators, cyclin D1 has been implicated most strongly in oncogenesis. This G1 cyclin is a putative proto-oncogene whose clonal rearrangement and/or amplification and mRNA overexpression occurs in several types of human neoplasias. We have now raised a series of monoclonal antibodies to human cyclin D1 and analysed its regulation at the protein level in 40 human tumour cell lines. We found that 12 cell lines displayed low or undetectable cyclin D1 protein level, while the remaining lines accumulated the protein to a level comparable to, or moderately higher than, that of four normal diploid non-immortalized cell types. The cell cycle-dependent oscillation and subcellular localization of cyclin D1 were similar in both tumour and normal cells. The protein localized to the nucleus of G1 cells, and it was reduced to immunocytochemically undetectable level in DNA-replicating cells. At the functional level, microinjection and electroporation of anti-D1 antibodies revealed that in most tumour cell lines studied, including those with amplification at the cyclin D1 locus, this cyclin is essential for cell cycle progression in G1. Some tumours, however, seem to have evolved mechanism(s) that enable them to bypass the requirement for functional cyclin D1.

• MeSH
• buněčný cyklus * MeSH
• cyklin D1 MeSH
• cykliny antagonisté a inhibitory   imunologie   metabolismus   MeSH
• imunohistochemie MeSH
• kultivované buňky MeSH
• lidé MeSH
• monoklonální protilátky MeSH
• nádorové buňky kultivované MeSH
• onkogenní proteiny antagonisté a inhibitory   imunologie   metabolismus   MeSH
• subcelulární frakce metabolismus   MeSH
• Check Tag
• lidé MeSH

Recent evidence from genetic studies suggests that abnormalities of some of the members of the cyclin superfamily may be intimately associated with tumourigenesis, most likely through deregulation of the cell cycle control. In an attempt to elucidate the potential role of cyclin D1 (a gene located within the 11q13 amplicon and a candidate BCL-1, PRAD-1 oncogene) in the pathogenesis of human neoplasias, we have developed and characterized a novel monoclonal antibody specifically recognizing cyclin D1 protein in various assays including immunohistochemistry on frozen and paraffin sections. Using the DCS-6 antibody as a tool, we now show a characteristic cell cycle-dependent variation of the cyclin D1 protein in human cultured cells and report on the first immunohistochemical study of this G1 cyclin in a range of normal human tissues and breast carcinomas. Analysis of normal tissues revealed generally low levels of cyclin D1 protein, mainly restricted to the proliferative zones of some epithelial tissues, and the lack of its expression in several human tissues including lymph nodes, spleen, and tonsils. In contrast, pronounced overexpression/nuclear accumulation of cyclin D1 was found in 37 per cent of cases in a series of 35 primary ductal carcinomas of the breast. We conclude that the DCS-6 antibody provides a potentially useful tool for the establishment of simple methods suitable for verifying any diagnostic and/or prognostic value of this novel marker on large series of histological specimens and opens the way for biochemical, immunocytochemical, and immunohistochemical studies of the role played by cyclin D1 aberrations in human oncogenesis.

• MeSH
• buněčný cyklus fyziologie   MeSH
• cyklin D1 MeSH
• cykliny * analýza   genetika   MeSH
• DNA analýza   MeSH
• exprese genu MeSH
• imunoenzymatické techniky MeSH
• kultivované buňky MeSH
• lidé MeSH
• monoklonální protilátky imunologie   MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• nádorové proteiny * analýza   MeSH
• nádory prsu * chemie   MeSH
• onkogenní proteiny * analýza   genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH

• MeSH
• cyklin D1 genetika   MeSH
• finanční podpora výzkumu jako téma MeSH
• geny erbB-2 genetika   MeSH
• lidé MeSH
• nádory prsu genetika   MeSH
• Pagetova nemoc prsu genetika   patologie   MeSH
• receptor erbB-2 analýza   genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH

Mammary analogue secretory carcinoma of salivary gland origin (MASC) is a recently described tumor resembling secretory carcinoma of the breast characterized by strong S-100 protein, mammaglobin, and vimentin immunoexpression and which harbors a t(12;15) (p13;q25) translocation resulting in ETV6-NTRK3 fusion product. Histologically, conventional MASC displays bland histomorphology and a lobulated growth pattern and is often composed of microcystic, tubular, and solid structures with abundant eosinophilic homogenous or bubbly secretions. Colloid-like secretory material stains positively for periodic acid-Schiff with and without diastase as well as for Alcian Blue. We present for the first time, 3 patients with MASC of the parotid gland in which high-grade (HG) transformation developed in each case characterized by an accelerated clinical course and poor outcome. The HG component revealed strong membrane staining for EGFR and β-catenin, cytoplasmic/nuclear staining for S-100 protein, and nuclear staining for cyclin-D1, whereas HER-2/neu was absent. Analysis for the presence of the ETV6-NTRK3 fusion transcript revealed positivity in both HG and low-grade component of MASC in 2 of the 3 studied cases. The tumor in case 2 was negative in both its elements for the t(12;15) translocation, but ETV6 gene rearrangement was detected in both components in all 3 cases. Analysis of TP53 and CTNNB1 gene mutations in the HG component of MASCs as well as detection of copy number aberration of EGFR and CCND1 gene did not harbor any abnormalities. All 3 patients with HG-transformed MASC died of disseminated disease within 2 to 6 years after diagnosis. Recognizing HG-transformed MASC and testing for ETV6 rearrangement may be of potential value in patient treatment, because the presence of the ETV6-NTRK3 translocation may represent a therapeutic target in MASC.

• MeSH
• beta-katenin analýza   genetika   MeSH
• biopsie MeSH
• časové faktory MeSH
• cyklin D1 analýza   genetika   MeSH
• erbB receptory analýza   genetika   MeSH
• fatální výsledek MeSH
• fúzní onkogenní proteiny genetika   MeSH
• imunohistochemie MeSH
• karcinom chemie   genetika   sekundární   terapie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• nádorová transformace buněk genetika   patologie   MeSH
• nádorové biomarkery analýza   genetika   MeSH
• nádorový supresorový protein p53 genetika   MeSH
• nádory příušní žlázy chemie   genetika   patologie   terapie   MeSH
• prognóza MeSH
• senioři MeSH
• stupeň nádoru MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH

D-type cyclins, in association with the cyclin-dependent kinases Cdk4 or Cdk6, promote progression through the G1 phase of the cell cycle by phosphorylating the retinoblastoma protein (RB). The activities of Cdk4 and Cdk6 are constrained by inhibitors such as p16, the product of the CDKN2 gene on human chromosome 9p21 (refs 12-14). The frequent deletion or mutation of CDKN2 in tumour cells suggests that p16 acts as a tumour suppressor. We show that wild-type p16 arrests normal diploid cells in late G1, whereas a tumour-associated mutant of p16 does not. Significantly, the ability of p16 to induce cell-cycle arrest is lost in cells lacking functional RB, including primary fibroblasts from Rb-/- mouse embryos. Thus, loss of p16, overexpression of D-cyclins and loss of RB have similar effects on G1 progression, and may represent a common pathway to tumorigenesis.

• MeSH
• buněčný cyklus * fyziologie   MeSH
• cyklin D1 MeSH
• cyklin-dependentní kinasa 4 MeSH
• cyklin-dependentní kinasa 6 MeSH
• cyklin-dependentní kinasy * MeSH
• cykliny fyziologie   MeSH
• Escherichia coli MeSH
• G1 fáze fyziologie   MeSH
• inhibitor p16 cyklin-dependentní kinasy MeSH
• klonování DNA MeSH
• kultivované buňky MeSH
• lidé MeSH
• mikroinjekce MeSH
• mutace MeSH
• myši inbrední BALB C MeSH
• myši MeSH
• nádorové buňky kultivované MeSH
• onkogenní proteiny fyziologie   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   MeSH
• protoonkogenní proteiny * MeSH
• rekombinantní proteiny metabolismus   MeSH
• retinoblastomový protein * fyziologie   MeSH
• transportní proteiny fyziologie   genetika   MeSH
• tumor supresorové geny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH

The product of the retinoblastoma susceptibility gene, pRb, acts as a tumor suppressor and loss of its function is involved in the development of various types of cancer. DNA tumor viruses are supposed to disturb the normal regulation of the cell cycle by inactivating pRb. However, a direct function of pRb in regulation of the cell cycle has hitherto not been shown. We demonstrate here that the cell cycle-dependent expression of one of the G1-phase cyclins, cyclin D1, is dependent on the presence of a functional Rb protein. Rb-deficient tumor cell lines as well as cells expressing viral oncoproteins (large tumor antigen of simian virus 40, early region 1A of adenovirus, early region 7 of papillomavirus) have low or barely detectable levels of cyclin D1. Expression of cyclin D1, but not of cyclins A and E, is induced by transfection of the Rb gene into Rb-deficient tumor cells. Cotransfection of a reporter gene under the control of the D1 promoter, together with the Rb gene, into Rb-deficient cell lines demonstrates stimulation of the D1 promoter by Rb, which parallels the stimulation of endogenous cyclin D1 gene expression. Our finding that pRb stimulates expression of a key component of cell cycle control, cyclin D1, suggests the existence of a regulatory loop between pRb and cyclin D1 and extends existing models of tumor suppressor function.

• MeSH
• buněčný cyklus * MeSH
• cyklin D1 MeSH
• cykliny genetika   metabolismus   MeSH
• DNA primery chemie   MeSH
• lidé MeSH
• messenger RNA genetika   MeSH
• molekulární sekvence - údaje MeSH
• nádorové buňky kultivované MeSH
• onkogenní proteiny genetika   metabolismus   MeSH
• promotorové oblasti (genetika) MeSH
• regulace genové exprese MeSH
• retinoblastomový protein * metabolismus   MeSH
• sekvence nukleotidů MeSH
• techniky in vitro MeSH
• Check Tag
• lidé MeSH

Loss of G(1)-S control and aberrations of the p16(Ink4a)-cyclin D1/cyclin-dependent kinase (CDK) 4(6)-pRb-E2F-cyclin E/CDK2 pathway are common in human cancer. Previous studies showed that oncogene-induced aberrant proliferation, such as on cyclin E overexpression, causes DNA damage and checkpoint activation. Here, we show that, in a series of human colorectal adenomas, those with deregulation of cyclin D1 and/or p16(Ink4a) showed little evidence of constitutive DNA damage response (DDR), contrary to cyclin E-overexpressing higher-grade cases. These observations were consistent with diverse cell culture models with differential defects of retinoblastoma pathway components, as overexpression of cyclin D1 or lack of p16(Ink4a), either alone or combined, did not elicit detectable DDR. In contrast, inactivation of pRb, the key component of the pathway, activated the DDR in cultured human or mouse cells, analogous to elevated cyclin E. These results highlight differential effect of diverse oncogenic events on driving the 'cancer cell cycles' and their ability to deregulate the replication-driving CDK2 kinase and to alarm the DDR as a potential anticancer barrier in accordance with their hierarchical positions along the retinoblastoma pathway. Our data provide new insights into oncogene-evoked DDR in human tumorigenesis, with potential implications for individualized management of tumors with elevated cyclin D1 versus cyclin E, due to their distinct clinical variables and biological behavior.

• MeSH
• cyklin D1 fyziologie   MeSH
• cyklin E fyziologie   MeSH
• cyklin-dependentní kinasa 2 fyziologie   MeSH
• geny p53 MeSH
• inhibitor p16 cyklin-dependentní kinasy fyziologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory etiologie   genetika   MeSH
• poškození DNA * MeSH
• retinoblastomový protein * fyziologie   MeSH
• transkripční faktor E2F1 fyziologie   MeSH
• Check Tag
• lidé MeSH