PIK3CA is implicated as an oncogene in ovarian cancer

Abstract

Ovarian cancer is the leading cause of death from gynecological malignancy and the fourth leading cause of cancer death among American women 1 , yet little is known about its molecular aetiology. Studies using comparative genomic hybridization (CGH) have revealed several regions of recurrent, abnormal, DNA sequence copy number 2, 3, 4 that may encode genes involved in the genesis or progression of the disease. One region at 3q26 found to be increased in copy number in approximately 40% of ovarian 2 and other 5 cancers contains PIK3CA , which encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3-kinase). The association between PIK3CA copy number and PI3-kinase activity makes PIK3CA a candidate oncogene because a broad range of cancer-related functions have been associated with PI3-kinase mediated signalling 6 . These include proliferation 7 , glucose transport and catabolism 8 , cell adhesion 9 , apoptosis 10 , RAS signalling 6 and oncogenic transformation 11, 12, 13, 14 . In addition, downstream effectors of PI3-kinase, AKT1 and AKT2 , have been found to be amplified 15, 16 or activated 17 in human tumours, including ovarian cancer. We show here that PIK3CA is frequently increased in copy number in ovarian cancers, that the increased copy number is associated with increased PIK3CA transcription, p110α protein expression and PI3-kinase activity and that treatment with the PI3-kinase inhibitor LY294002 decreases proliferation and increases apoptosis. Our observations suggest PIK3CA is an oncogene that has an important role in ovarian cancer.

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Figure 1: Analysis of PIK3CA relative copy number.
Figure 2: Quantitative PCR analyses of PIK3CA transcription.
Figure 3: Western-blot analysis of p85 and p110α expression.
Figure 4: PI3-kinase activity.
Figure 5: Effect of LY294002 on cell proliferation and apoptosis.

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Acknowledgements

We thank D. LePaslier for YAC clones used in early aspects of this study; R. Bast, R. Taetle and N. Auersperg for melanoma and ovarian cancer cell lines, IOSE and ovarian tumours; and H. Kahn, C. Chen and R. Lapushin for technical support. L.S. was supported by training grants NIH Radiation Oncology Research Training Grant CA09215 and UC Systemwide Biotechnology Research and Education Program Grant 96-03. This work was performed with support from USPHS grant P01-CA64602, DOE contract DE-AC-03-76SF00098 and Vysis.

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Correspondence to Joe W. Gray.

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Shayesteh, L., Lu, Y., Kuo, W. et al. PIK3CA is implicated as an oncogene in ovarian cancer. Nat Genet 21, 99–102 (1999). https://doi.org/10.1038/5042

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