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Functional Analysis of PIK3CA Gene Mutations in Human Colorectal Cancer

¹ Department of Gastroenterology, Graduate School of Medicine and ² Clinical Research Center, University of Tokyo Hospital, Bunkyo-ku; ³ Division of Gastroenterology, Institute for Adult Diseases, Asahi Life Foundation, Nishi-Shinjuku, Shinjuku-ku, Tokyo Japan; and ⁴ Division of Molecular Genetics, Institute for Enzyme Research, University of Tokushima, Tokushima City, Tokushima Japan

Requests for reprints: Fumihiko Kanai, Department of Gastroenterology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-3815-5411; Fax: 81-3-3814-0021; E-mail: kanaif-int{at}h.u-tokyo.ac.jp.

Mutations in the PIK3CA gene, which encodes the p110 catalytic subunit of phosphatidylinositol 3-kinase (PI3K), have been reported in human cancers, including colorectal cancer. Most of the mutations cluster at hotspots within the helical and kinase domains. Whereas H1047R, one of the hotspot mutants, is reported to have elevated lipid kinase activity, the functional consequences of other mutations have not been examined. In this study, we examined the effects of colon cancer–associated PIK3CA mutations on the lipid kinase activity in vitro, activation of the downstream targets Akt and p70S6K in vivo and NIH 3T3-transforming ability. Of eight mutations examined, all showed increased lipid kinase activity compared with wild-type p110. All the mutants strongly activated Akt and p70S6K compared with wild-type p110 as determined by immunoblotting using phospho-specific antibodies. These mutants also induced morphologic changes, loss of contact inhibition, and anchorage-independent growth of NIH 3T3 cells. The hotspot mutations examined in this study, E542K, E545K, and H1047R, all had high enzymatic and transforming activities. These results show that almost all the colon cancer–associated PIK3CA mutations are functionally active so that they are likely to be involved in carcinogenesis.

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