Abstract
IntroductionPhosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival, and motility. Even though PIK3CA amplification and somatic mutation have been reported previously in various kinds of human cancers, the genetic change in PIK3CA in human breast cancer has not been clearly identified.MethodsFifteen breast cancer cell lines and 92 primary breast tumors (33 with matched normal tissue) were used to check somatic mutation and gene copy number of PIK3CA. For the somatic mutation study, we specifically checked exons 1, 9, and 20, which have been reported to be hot spots in colon cancer. For the analysis of the gene copy number, we used quantitative real-time PCR and fluorescence in situ hybridization. We also treated several breast cancer cells with the PIK3CA inhibitor LY294002 and compared the apoptosis status in cells with and without PIK3CA mutation.ResultsWe identified a 20.6% (19 of 92) and 33.3% (5 of 15) PIK3CA somatic mutation frequency in primary breast tumors and cell lines, respectively. We also found that 8.7% (8 of 92) of the tumors harbored a gain of PIK3CA gene copy number. Only four cases in this study contained both an increase in the gene copy number and a somatic mutation. In addition, mutation of PIK3CA correlated with the status of Akt phosphorylation in some breast cancer cells and inhibition of PIK3CA-induced increased apoptosis in breast cancer cells with PIK3CA mutation.ConclusionSomatic mutation rather than a gain of gene copy number of PIK3CA is the frequent genetic alteration that contributes to human breast cancer progression. The frequent and clustered mutations within PIK3CA make it an attractive molecular marker for early detection and a promising therapeutic target in breast cancer.
Highlights
Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival, and motility
Somatic mutation rather than a gain of gene copy number of PIK3CA is the frequent genetic alteration that contributes to human breast cancer progression
PIK3CA was found to Bacterial artificial chromosome (BAC) = bacterial artificial chromosome; DAPI = 4',6-diamidino-2-phenylindole; Fluorescence in situ hybridization (FISH) = fluorescence in situ hybridization; H & E = hematoxylin and eosin; PI3K = phosphatidylinositol 3-kinase
Summary
Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases that regulate signaling pathways involved in cell proliferation, adhesion, survival, and motility. Phosphatidylinositol 3-kinases (PI3Ks) are a group of lipid kinases composed of 85-kDa and 110-kDa subunits. The 85kDa subunit lacks PI3K activity and acts as adaptor, coupling the 110-kDa subunit (P110) to activated protein tyrosine kinases and generating second messengers by phosphorylating membrane inositol lipids at the D3 position. The resulting phosphatidylinositol derivatives permit activation of downstream effectors that are involved in cell proliferation, survival, metabolism, cytoskeletal reorganization, and membrane trafficking [1,2]. PIK3CA, the gene encoding the 110-kDa subunit of PI3K, was mapped to 3q26, an area amplified in various human cancers including ovarian, head and neck, breast, urinary tract, and cervical cancers [3,4,5].
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