Abstract：
:The selective pressures leading to cancers with mutations in both KRAS and PIK3CA are unclear. Here, we show that somatic cell knockin of both KRAS G12V and oncogenic PIK3CA mutations in human breast epithelial cells results in cooperative activation of the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways in vitro, and leads to tumor formation in immunocompromised mice. Xenografts from double-knockin cells retain single copies of mutant KRAS and PIK3CA, suggesting that tumor formation does not require increased copy number of either oncogene, and these results were also observed in human colorectal cancer specimens. Mechanistically, the cooperativity between mutant KRAS and PIK3CA is mediated in part by Ras/p110α binding, as inactivating point mutations within the Ras-binding domain of PIK3CA significantly abates pathway signaling. In addition, Pdk1 activation of the downstream effector p90RSK is also increased by the combined presence of mutant KRAS and PIK3CA. These results provide new insights into mutant KRAS function and its role in carcinogenesis.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Wang GM,Wong HY,Konishi H,Blair BG,Abukhdeir AM,Gustin JP,Rosen DM,Denmeade SR,Rasheed Z,Matsui W,Garay JP,Mohseni M,Higgins MJ,Cidado J,Jelovac D,Croessmann S,Cochran RL,Karnan S,Konishi Y,Ota A,Hosokawa Y,Argadoi
10.1158/0008-5472.CAN-12-1578subject
Has Abstractpub_date
2013-06-01 00:00:00pages
3248-61issue
11eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-12-1578journal_volume
73pub_type
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