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Amplification of Chromosome 1q Genes Encoding the Phosphoinositide Signalling Enzymes PI4KB, AKT3, PIP5K1A and PI3KC2B in Breast Cancer.

Waugh MG - J Cancer (2014)

Bottom Line: Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme.Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation.By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples.

View Article: PubMed Central - PubMed

Affiliation: Lipid and Membrane Biology Group, Institute for Liver and Digestive Health, UCL, Royal Free Campus, Rowland Hill Street, London, NW3 2PF United Kingdom.

ABSTRACT
Little is known about the possible oncogenic roles of genes encoding for the phosphatidylinositol 4-kinases, a family of enzymes that regulate an early step in phosphoinositide signalling. To address this issue, the mutational status of all four human phosphatidylinositol 4-kinases genes was analyzed across 852 breast cancer samples using the COSMIC data resource. Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme. Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation. By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples. The PI4KB, PIP5K1A, PI3KC2B and AKT3 genes are related in that they all localize to chromosome 1q which is often structurally and numerically abnormal in breast cancer. These results demonstrate that a gene quartet encoding a potential phosphoinositide signalling pathway is amplified in a subset of breast cancers.

No MeSH data available.


Related in: MedlinePlus

Expression of phosphoinositide signalling proteins in normal breast tissue and in ductal carcinoma. Images were obtained by immunohistochemical staining of paraffin-embedded tissue samples using isoform-specific antibodies directed against the protein products of PI4KB, PIP5K1A, PIK3C2B and AKT3. Antibody binding appears as brown/black staining on a background of blue hematoxylin counterstain. All images are from the Human Protein Atlas.
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Figure 6: Expression of phosphoinositide signalling proteins in normal breast tissue and in ductal carcinoma. Images were obtained by immunohistochemical staining of paraffin-embedded tissue samples using isoform-specific antibodies directed against the protein products of PI4KB, PIP5K1A, PIK3C2B and AKT3. Antibody binding appears as brown/black staining on a background of blue hematoxylin counterstain. All images are from the Human Protein Atlas.

Mentions: Finally, the Human Protein Atlas 20, 21 (www.proteinatlas.org) was surveyed to search if there was any evidence for upregulated expression of the enzyme products of the four identified genes in breast cancer tissues. In normal breast tissue (Figure 6), the strongest intensity of immunohistochemical staining for PtdIns 4-kinase IIIβ, PtdIns4P 5-Kinase 1α, Akt3 and phosphoinositide 3-kinase C2β was in the ductal tissue. Increased expression of all four proteins was observed in ductal carcinomas and this was most pronounced for the PtdIns 4-kinase IIIβ and phosphoinositide 3-kinase C2β proteins. For the eleven antibody-stained breast cancer tumour samples in the human protein atlas, the intensity of anti-PtdIns 4-kinase IIIβ staining was classified as moderate or strong in 8/11 cases. Similarly for the PIK3C2B gene product, 8/11 patient samples exhibited strong expression. Immunohistochemical staining for PIP5K1A was less strong with only low level immunoreactivity detected in 7/11 tumours. This mirrored the immunohistochemical data for Akt3 where 8/12 samples were determined to have low expression of this protein and only one sample exhibited moderate Akt3 overexpression. However, while these immunohistochemical results partly support the genomic data they need to be treated with caution as they derive from a much lower number of patient samples and from tumours where the chromosome 1q status was not known.


Amplification of Chromosome 1q Genes Encoding the Phosphoinositide Signalling Enzymes PI4KB, AKT3, PIP5K1A and PI3KC2B in Breast Cancer.

Waugh MG - J Cancer (2014)

Expression of phosphoinositide signalling proteins in normal breast tissue and in ductal carcinoma. Images were obtained by immunohistochemical staining of paraffin-embedded tissue samples using isoform-specific antibodies directed against the protein products of PI4KB, PIP5K1A, PIK3C2B and AKT3. Antibody binding appears as brown/black staining on a background of blue hematoxylin counterstain. All images are from the Human Protein Atlas.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4216804&req=5

Figure 6: Expression of phosphoinositide signalling proteins in normal breast tissue and in ductal carcinoma. Images were obtained by immunohistochemical staining of paraffin-embedded tissue samples using isoform-specific antibodies directed against the protein products of PI4KB, PIP5K1A, PIK3C2B and AKT3. Antibody binding appears as brown/black staining on a background of blue hematoxylin counterstain. All images are from the Human Protein Atlas.
Mentions: Finally, the Human Protein Atlas 20, 21 (www.proteinatlas.org) was surveyed to search if there was any evidence for upregulated expression of the enzyme products of the four identified genes in breast cancer tissues. In normal breast tissue (Figure 6), the strongest intensity of immunohistochemical staining for PtdIns 4-kinase IIIβ, PtdIns4P 5-Kinase 1α, Akt3 and phosphoinositide 3-kinase C2β was in the ductal tissue. Increased expression of all four proteins was observed in ductal carcinomas and this was most pronounced for the PtdIns 4-kinase IIIβ and phosphoinositide 3-kinase C2β proteins. For the eleven antibody-stained breast cancer tumour samples in the human protein atlas, the intensity of anti-PtdIns 4-kinase IIIβ staining was classified as moderate or strong in 8/11 cases. Similarly for the PIK3C2B gene product, 8/11 patient samples exhibited strong expression. Immunohistochemical staining for PIP5K1A was less strong with only low level immunoreactivity detected in 7/11 tumours. This mirrored the immunohistochemical data for Akt3 where 8/12 samples were determined to have low expression of this protein and only one sample exhibited moderate Akt3 overexpression. However, while these immunohistochemical results partly support the genomic data they need to be treated with caution as they derive from a much lower number of patient samples and from tumours where the chromosome 1q status was not known.

Bottom Line: Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme.Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation.By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples.

View Article: PubMed Central - PubMed

Affiliation: Lipid and Membrane Biology Group, Institute for Liver and Digestive Health, UCL, Royal Free Campus, Rowland Hill Street, London, NW3 2PF United Kingdom.

ABSTRACT
Little is known about the possible oncogenic roles of genes encoding for the phosphatidylinositol 4-kinases, a family of enzymes that regulate an early step in phosphoinositide signalling. To address this issue, the mutational status of all four human phosphatidylinositol 4-kinases genes was analyzed across 852 breast cancer samples using the COSMIC data resource. Point mutations in the phosphatidylinositol 4-kinase genes were uncommon and appeared in less than 1% of the patient samples however, 62% of the tumours had increases in gene copy number for PI4KB which encodes the phosphatidylinositol 4-kinase IIIbeta isozyme. Extending this analysis to subsequent enzymes in the phosphoinositide signalling cascades revealed that the only PIP5K1A, PI3KC2B and AKT3 genes exhibited similar patterns of gene copy number variation. By comparison, gene copy number increases for established oncogenes such as EGFR and HER2/Neu were only evident in 20% of the samples. The PI4KB, PIP5K1A, PI3KC2B and AKT3 genes are related in that they all localize to chromosome 1q which is often structurally and numerically abnormal in breast cancer. These results demonstrate that a gene quartet encoding a potential phosphoinositide signalling pathway is amplified in a subset of breast cancers.

No MeSH data available.


Related in: MedlinePlus