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PIK3CA is implicated as an oncogene in ovarian cancer
1UCSF Cancer Center, University of California, San Francisco 941430-0808, USA.
Abstract:
Ovarian cancer is the leading cause of death from gynecological malignancy and the fourth leading cause of cancer death among American women, 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 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 and others cancers contains PIK3CA, which encodes the p110alpha 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. These include proliferation, glucose transport and catabolism, cell adhesion, apoptosis, RAS signalling and oncogenic transformation. In addition, downstream effectors of PI3-kinase, AKT1 and AKT2, have been found to be amplified or activated 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, p110alpha 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.
Insights
The PIK3CA gene, often amplified in ovarian cancers, drives tumor growth by increasing phosphatidylinositol 3-kinase (PI3-kinase) activity. Inhibiting this pathway slows cancer cell proliferation and promotes apoptosis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Ovarian cancer is a leading cause of cancer death with poorly understood molecular drivers.
- Comparative genomic hybridization (CGH) studies identify DNA copy number alterations in cancer development.
- The 3q26 region, amplified in ~40% of ovarian cancers, harbors the PIK3CA gene.
Purpose of the Study:
- To investigate the role of PIK3CA in ovarian cancer.
- To determine if increased PIK3CA copy number correlates with gene expression, protein levels, and enzyme activity.
- To assess the therapeutic potential of PI3-kinase inhibition in ovarian cancer models.
Main Methods:
- Comparative genomic hybridization (CGH) to assess PIK3CA copy number.
- Quantitative PCR and Western blotting to measure PIK3CA transcription and p110alpha protein expression.
- Enzyme assays to determine PI3-kinase activity.
- In vitro treatment with PI3-kinase inhibitor LY294002.
Main Results:
- PIK3CA copy number is frequently increased in ovarian cancers.
- Increased PIK3CA copy number correlates with elevated PIK3CA transcription, p110alpha protein expression, and PI3-kinase activity.
- Inhibition of PI3-kinase with LY294002 reduced ovarian cancer cell proliferation and induced apoptosis.
Conclusions:
- PIK3CA is frequently amplified and activated in ovarian cancer.
- PIK3CA acts as an oncogene, playing a significant role in ovarian cancer progression.
- Targeting the PI3-kinase pathway represents a potential therapeutic strategy for ovarian cancer.