PIK3CA
Phosphatidyl 3-kinases (PI3K) are a family of lipid kinases involved in many cellular processes, including cell growth, proliferation, differentiation, motility, and survival. PI3K is a heterodimer composed of 2 subunits—an 85 kDa regulatory subunit (p85) and a 110 kDa catalytic subunit. The PIK3CA gene encodes p110α, one of the catalytic subunits.
PI3K converts PI(4,5)P2 [Phosphatidylinositol 4,5-bisphosphate] to PI(3,4,5)P3 [Phosphatidylinositol (3,4,5)-trisphosphate] on the inner leaflet of the cell membrane. PI(3,4,5)P3 recruits important downstream signaling proteins, such as AKT, to the cell membrane resulting in increased activity of these proteins.
Mutant PIK3CA has been implicated in the pathogenesis of several cancers, including colon cancer, gliomas, gastric cancer, breast cancer, endometrial cancer, and lung cancer (COSMIC; Samuels et al. 2004)
Figure 1. Schematic of the MAPK and PI3K pathways. . Growth factor binding to receptor tyrosine kinase results in activation of the MAPK signaling pathway (RAS-RAF-MEK-ERK) and the PI3K pathway (PI3K-AKT-mTOR). The letter "K" within the schema denotes the tyrosine kinase domain.
Last Updated: June 1, 2012
PIK3CA Mutations in Breast Cancer
Somatic mutations in PIK3CA have been found in a substantial fraction of breast cancers (see Table 1). PIK3CA mutations are positive prognostic factors in breast cancer (Cizkova et al. 2012; Janku et al. 2012).
| Gene Mutation | Invasive Breast Cancer | Hormone Receptor Positive (ER+ and/or PR+) Invasive Breast Cancer | HER2 positive Invasive Breast Cancer | Triple-negative Invasive Breast Cancer |
|---|---|---|---|---|
| PIK3CA | 26% (Saal et al. 2005; Stemke-Hale et al. 2008; O'Brien et al. 2010) | 34.5% (Saal et al. 2005; Stemke-Hale et al. 2008) | 22–31% (Saal et al. 2005; Stemke-Hale et al. 2008) | 8.3% (Stemke-Hale et al. 2008) |
These mutations usually occur within two "hotspot" areas within exon 9 (the helical domain) and exon 20 (the kinase domain).
| Gene | Exon | Location | Amino Acid Position | Amino Acid Change | Nucleotide Change | Frequency Among PIK3CA Mutant Breast Cancer (COSMIC) |
|---|---|---|---|---|---|---|
| PIK3CA | 9 | Helical domain | E542 | p.E542K | c.1624G>A | 11% |
| E545 | p.E545K | c.1633G>A | 20% | |||
| p.E545Q | c.1633G>C | <1% | ||||
| p.E545A | c.1634A>C | 1.5% | ||||
| p.E545G | c.1634A>G | <1% | ||||
| p.E545V | c.1634A>T | <1% | ||||
| Q546 | p.Q546K | c.1636C>A | <1% | |||
| p.Q546E | c.1636C>G | <1% | ||||
| p.Q546P | c.1637A>C | <1% | ||||
| p.Q546R | c.1637A>G | <1% | ||||
| p.Q546L | c.1637A>T | <1% | ||||
| p.D549N | c.1645G>A | <1% | ||||
| 20 | Kinase Domain | H1047 | p.H1047R | c.3140A>G | 55% | |
| p.H1047L | c.3140A>T | 5% |
Last Updated: June 8, 2012
PIK3CA-Associated Breast Cancer Clinical Trials
Great effort was made to include all clinical trials relevant for this mutation. However, the completeness of this information cannot be guaranteed.
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