DNA amplification at 11q13 in human cancer: from complexity to perplexity

Gaudray, Patrick; Szepetowski, Pierre; Escot, Chantal; Birnbaum, Daniel; Theillet, Charles

doi:10.1016/0165-1110(92)90018-5

Cited by 92 publications

(56 citation statements)

References 26 publications

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“…The prognostic discrepancy between cyclin D1 protein expression and gene ampli®cation analysis could be due to di erences in disease stages of patients in the various studies and the problem of de®ning a truly pathological cyclin D1 overexpression and not induced by mitogenes and steroids in receptor positive tumours . Furthermore, the large 11q13 amplicon contains genes in addition to cyclin D1 that in principles could be of pathogenetic importance in breast cancer (Schuuring et al, 1992a;Gaudray et al, 1992), although cyclin D1 is one of the most faithfully ampli®ed and expressed gene in the amplicon (Fantl et al, 1990;Lammie et al, 1991). We agree with Michalides et al (1996) that cyclin D1 expression will probably not turn to be an important prognostic marker in breast cancer because of the strong correlation to oestrogen receptor status.…”

Section: Discussionmentioning

confidence: 99%

Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein

et al. 1997

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Inactivation of the retinoblastoma protein (pRB) by mutations or abnormal phosphorylation is a mechanism by which tumour cells can subdue normal growth control. Among molecules involved in control of pRB phosphorylation, cyclin D1 and E have been found to be deregulated and overexpressed in various types of cancers. In order to study the cell cycle regulatory mechanisms in breast cancer, we have analysed the protein expression of cyclin D1 and E in 114 tumour specimens from patients with primary breast cancer using Western blotting. Twenty-®ve out of 34 tumours with overexpression of cyclin E showed uniform low cyclin D1 expression, and by immunohistochemical analysis of pRB we present evidence for the existence of pRB defects in approximately 40% of these tumours in contrast to no pRB defects in the other group of tumours. This result was supported by a high protein expression of the cyclindependent kinase inhibitor p16 in 44% of the tumours with high cyclin E and low D1 expression, and all immunohistochemical pRB defect tumours showed a high p16 protein level. Additionally, an abnormal low pRB phosphorylation in relation to a high proliferative activity and loss of heterozygosity of the retinoblastoma susceptibility gene locus were found in all but one tumour with immunohistochemical defect pRB. Interestingly, tumours with high cyclin E and low D1 expression were generally oestrogen receptor negative suggesting a role for cell cycle regulators in the mechanisms leading to oestrogen independent tumour growth. Furthermore, the prognosis di ered markedly for the patients in the various groups of tumours, indicating that the heterogeneous nature of breast cancer pathogenesis and the clinical course in part could be explained by di erent and distinctive sets of cell cycle defects.

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Section: Discussionmentioning

confidence: 99%

Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein

et al. 1997

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“…Clinical follow-up of tumors from our panels will be done to assess this point. Ampli®cation of the 11q13-14 region has been detected in 15 ± 25% of breast carcinomas (Gaudray et al, 1992). Such a process may alter the structure of chromosome arm 11q and lead to the loss of the remaining portion of the chromosome, creating LOH which could be falsely interpreted as the inactivation of a tumor suppressor gene.…”

Section: Correlation With Clinico-histological Parametersmentioning

confidence: 99%

Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions

et al. 1997

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To appreciate the involvement of known or potential susceptibility genes in sporadic breast tumors, we have searched for chromosomal deletions by studying loss of heterozygosity (LOH) at 43 microsatellite (CA) n markers from human chromosomes 10, 11 and 17, in 115 unselected consecutive samples of breast carcinoma with particular emphasis on speci®c regions. No site of consistent LOH was identi®ed on chromosome 10. Five regions of LOH were contained within bands q22-24 of chromosome 11 for which nearly 50% of the tumors had LOH at at least one marker. This region is thus a major site of deletion in breast cancer and several tumor suppressor genes seem to be involved. One of them may be the ataxia telangiectasia (ATM) gene which is located in one of the a ected regions. Five regions of LOH, one of which is within the BRCA1 gene area, were recognized along chromosome 17. LOH at three of these regions were found in highly proliferative tumors. When combined with a previous study of chromosome 13 with emphasis on BRCA2 and Rb1 genes, this work allowed to distinguish a total of 12 regions of LOH, variably a ected in breast tumors and correlated with prognostic parameters.

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“…Amplicons often contain several syntenic genes, such as an amplification of the 11q13 locus that encompasses FGF3, FGF4, and CYCD1 (Gaudray et al, 1992) or the amplification of the locus 12q13 that encompasses MDM2, CDK4, and GLI (Khatib et al, 1993). We now recognize that amplicons are stabilized in the human genome when they encompass several genes that provide a selective growth advantage to the cell.…”

Section: Introductionmentioning

confidence: 99%

The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis

et al. 2006

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The 19q13 amplicon in pancreatic cancer cells contains a novel pancreatic differentiation 2 (PD2) gene (accession number AJ401156), which was identified by differential screening analysis. PD2 is the human homologue of the RNA polymerase II-associated factor 1 (hPaf1). In yeast, Paf1 is part of the transcription machinery, acting as a docking protein in between the complexes Rad6-Bre1, COMPASS-Dot1p, and the phosphorylated carboxyl terminal domain of the RNA polymerase II. As such, Paf1 is directly involved in transcription elongation via histone H2B ubiquitination and histone H3 methylation. The PD2 sequence is highly conserved from Drosophila to humans with up to 98% identity between rodent and human, suggesting the functional importance of PD2/ hPaf1 to maintain cellular homeostasis. PD2 is a modular protein composed of RNA recognition motif, DEADboxes, an aspartic/serine (DS)-domain, a regulator of the chromosome condensation domain and myc-type helixloop-helix domains. Our results further showed that PD2 is a nuclear 80 kDa protein, which interacts with RNA polymerase II. In addition, we have demonstrated that the overexpression of PD2 in the NIH 3T3 cells result in enhanced growth rates in vitro and tumor formation in vivo. Altogether, this paper presents strong evidence that the overexpression of PD2/hPaf1 is involved in cancer development.

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DNA amplification at 11q13 in human cancer: from complexity to perplexity

Cited by 92 publications

References 26 publications

Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein

Deregulation of cyclin E and D1 in breast cancer is associated with inactivation of the retinoblastoma protein

Loss of heterozygosity in human breast carcinomas in the ataxia telangiectasia, Cowden disease and BRCA1 gene regions

The human homologue of the RNA polymerase II-associated factor 1 (hPaf1), localized on the 19q13 amplicon, is associated with tumorigenesis

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