Cyclin E overexpression and amplification in human tumours

Schraml, Peter; Bucher, Christoph; Bissig, Heidi; Nocito, Antonio; Haas, Philippe; Wilber, Kim; Seelig, Steven; Kononen, Juha; Mihatsch, Michael J.; Dirnhofer, Stefan; Sauter, Guido

doi:10.1002/path.1356

Cited by 136 publications

(104 citation statements)

References 21 publications

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“…73 Interestingly, we have not detected any BRCA1/2 carcinoma showing CCNE amplification, 34 indicating that in hereditary breast carcinoma CCNE amplification is a rare event, as previously reported for sporadic cases. 74 Based on their cell-cycle regulatory defects, the phenotypes of BRCA1 and BRCA2 carcinomas are similar to those proposed by Landberg, 75 but with fewer markers differentiating at least two subgroups of sporadic breast cancer. One of them, the BRCA2 carcinomas, was characterized by estrogen receptor-positivity and high cyclin D1 and p27, and seemed to induce cell proliferation through a preserved Rb pathway.…”

Section: Alterations In Cell-cycle Regulationsupporting

confidence: 58%

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

2005

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Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of highgrade, highly proliferating, estrogen receptor-and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor-and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma. Keywords: hereditary breast cancer; BRCA1; BRCA2; molecular pathology; histopathology; immunohistochemistry It is currently estimated that 5-10% of all breast cancers are hereditary and attributable to mutations in high-penetrance susceptibility genes, but only two of these have been identified: BRCA1 (OMIM 113705) 1 and BRCA2 (OMIM 600185). 2 BRCA1 mutations are associated with families with breast and ovarian cancer, while families with male breast tumors are associated with mutations in the BRCA2 gene.While early estimates suggested that BRCA1 and BRCA2 mutations were responsible for 75% of multiple-case breast cancer families and for the majority of families with multiple breast and ovarian cancers, 3,4 recent data have shown that these percentages may have been overestimated. In fact, the percentage of high-risk families associated with mutations in these genes seems to be around 25% in all series investigated, including the Spanish population. 5 Mutations are found in a high percentage (about 45%) of families with breast and ovarian tumors, while the mutation rate in families with only breast can...

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Section: Alterations In Cell-cycle Regulationsupporting

confidence: 58%

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

2005

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“…20 One thing to be noted is that cyclin E protein is accumulated in the tumor cells in a considerable proportion of colorectal cancers. 21 On the basis of these observations, in the present study, we evaluated the regulation of Parkin gene expression in association with cell cycle regulation in colonic epithelial cells.…”

Section: Uiccmentioning

confidence: 99%

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

Ikeuchi

Marusawa

Fujiwara

et al. 2009

Intl Journal of Cancer

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Parkin has a critical role in the ubiquitin-proteasome system as an E3-ligase targeting several substrates. Our recent finding that Parkin-deficient mice are susceptible to tumorigenesis provided evidence that Parkin is a tumor suppressor gene. Dysfunction of the Parkin gene is frequently observed in various human cancers, but the mechanism underlying the cell cycle disruption induced by Parkin dysfunction that leads to carcinogenesis is not known. Here, we demonstrated that Parkin expression in colonic epithelial cells is regulated in a cell cycle-associated manner. Epidermal growth factor (EGF) stimulation upregulated Parkin gene expression in human colon cells. Inhibition of the phosphoinositide 3-kinase [PI(3)K]-Akt-dependent pathways suppressed growth factorinduced Parkin expression. The expression of alternatively spliced Parkin isoforms with various deletions spanning exons 3-6 was detected in 18 of 43 (42%) human colorectal cancer tissues. Wildtype Parkin induced the degradation of cyclin E protein, but the alternatively spliced Parkin identified in colon cancers showed defective proteolysis of cyclin E. These findings indicate that Parkin expression is induced by growth factor stimulation and is involved in the cell cycle regulation of colon cells. Tumor-specific expression of alternatively spliced Parkin isoforms might contribute to enhanced cell proliferation through the attenuation of proteolysismediated cyclin E regulation in human colorectal cancers. ' UICCKey words: Parkin; colorectal cancer; cyclin E; cell cycle; EGF Parkin functions in the ubiquitin-proteasome system as an E3 ligase, facilitating the ubiquitination of target proteins. [1][2][3] Parkin is developmentally regulated with induced expression during cell differentiation, and little to no expression in immature cells. 4 Several putative candidate substrates of Parkin-mediated proteolysis have been identified, including a-synphilin, a-synuclein interacting protein, synphilin-1 and Pael-R. 5,6 Recently, it was revealed that deficiency of Parkin potentiates the accumulation of cyclin E protein in cultured postmitotic neurons exposed to the glutamatergic excitotoxin kainate, suggesting that the cell cycle regulator, cyclin E, is a putative substrate of the Parkin ubiquitin ligase complex in neurons. 7 Since Parkin was first identified as a gene implicated in autosomal recessive juvenile Parkinsonism, one form of familial Parkinson disease, 8 attention has been focused on unveiling the role of Parkin in neurons. The expression and regulation of Parkin in epithelial cells as well as the role of Parkin in cell cycle regulation, however, has not been clarified.A loss of heterozygosity within chromosomal region 6q25-q27 containing the Parkin gene is frequently observed in various human tumors, including ovarian, 9-11 breast, 12 renal 13 and lung cancers. 14,15 In addition, the Parkin gene is frequently deleted in breast, ovarian and liver cancers. [16][17][18] We recently demonstrated that Parkin-deficient mice lacking exon 3 of the Parkin ge...

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“…36 One study reported no association between positive VEGF staining and tumour size, grade, ER and PR status. 37 In a further study which determined total and free VEGF protein levels in breast cancer tumour cytosol, 38 total VEGF levels were found to be independent predictors of disease free and overall survival.…”

Section: Discussionmentioning

confidence: 99%

Influence of VEGF‐A gene variation and protein levels in breast cancer susceptibility and severity

Balasubramanian

Cox

Cross

et al. 2007

Intl Journal of Cancer

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Vascular endothelial growth factor‐A (VEGF‐A) plays an important role in tumour angiogenesis and cancer progression. VEGF gene variation may influence VEGF levels and therefore cancer susceptibility and progression. We studied the role of VEGF single nucleotide polymorphisms and haplotypes in breast cancer susceptibility and severity. We also studied the relationships of VEGF SNPs with circulating VEGF levels in healthy volunteers and protein expression in breast cancers. Single nucleotide polymorphisms (SNPs) in the regulatory regions of the VEGF gene were genotyped by high throughput methods in ∼500 breast cancer cases and 500 appropriate controls. Haplotype frequencies were inferred using methods based on the Expectation Maximisation algorithm. The effect of VEGF genotypes on serum and plasma VEGF levels were studied in another cohort of healthy individuals. A semi‐quantitative assessment of VEGF protein expression on tissue micro arrays (TMA) constructed from ∼300 breast cancer samples was performed and compared with VEGF genotypes and with histopathological parameters and survival in breast cancer. The −460T/+405C/−7C/936C haplotype in the VEGF gene was found to be associated with decreased breast cancer risk (p = 0.029). The −7C>T polymorphism may influence overall breast cancer survival (p = 0.027). Individual polymorphisms however did not affect breast cancer susceptibility. There was no association between the individual polymorphisms and circulating VEGF levels in healthy volunteers and VEGF expression on the breast cancer micro array. VEGF expression in breast cancers was however associated with high grade (p = 0.002) and ER negative tumours (p = 0.03). © 2007 Wiley‐Liss, Inc.

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Cyclin E overexpression and amplification in human tumours

Cited by 136 publications

References 21 publications

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

Attenuation of proteolysis‐mediated cyclin E regulation by alternatively spliced Parkin in human colorectal cancers

Influence of VEGF‐A gene variation and protein levels in breast cancer susceptibility and severity

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