Cancer-specific mutations in PIK3CA are oncogenic in vivo

被引:360
作者
Bader, AG [1 ]
Kang, SY [1 ]
Vogt, PK [1 ]
机构
[1] Scripps Res Inst, Dept Mol & Expt Med, La Jolla, CA 92037 USA
关键词
chorioallantoic membrane; hemangiosarcoma; phosphaticlylinositol; 3-kinase; p110;
D O I
10.1073/pnas.0510857103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The PIK3CA gene, coding for the catalytic subunit p110 alpha of class IA phosphatidylinositol 3-kinases (PI3s), is frequently mutated in human cancer. Mutated p110 alpha proteins show a gain of enzymatic function in vitro and are oncogenic in cell culture. Here, we show that three prevalent mutants of p110 alpha, E542K, E545K, and H1047R, are oncogenic in vivo. They induce tumors in the chorioallantoic membrane of the chicken embryo and cause hemangiosarcomas in the animal. These tumors are marked by increased angiogenesis and an activation of the Akt pathway. The target of rapamycin inhibitor RAD001 blocks tumor growth induced by the H1047R p110 alpha mutant. The in vivo oncogenicity of PIK3CA mutants in an avian species strongly suggests a critical role for these mutated proteins in human malignancies.
引用
收藏
页码:1475 / 1479
页数:5
相关论文
共 32 条
[1]   The catalytic subunit of phosphoinositide 3-kinase: Requirements for oncogenicity [J].
Aoki, M ;
Schetter, C ;
Himly, M ;
Batista, O ;
Chang, HW ;
Vogt, PK .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2000, 275 (09) :6267-6275
[2]   The PIK3CA gene is mutated with high frequency in human breast cancers [J].
Bachman, KE ;
Argani, P ;
Samuels, Y ;
Silliman, N ;
Ptak, J ;
Szabo, S ;
Konishi, H ;
Karakas, B ;
Blair, BG ;
Lin, C ;
Peters, BA ;
Velculescu, VE ;
Park, BH .
CANCER BIOLOGY & THERAPY, 2004, 3 (08) :772-775
[3]   Inhibition of protein synthesis by Y box-binding protein 1 blocks oncogenic cell transformation [J].
Bader, AG ;
Vogt, PK .
MOLECULAR AND CELLULAR BIOLOGY, 2005, 25 (06) :2095-2106
[4]   Mutations of PIK3CA in anaplastic oligodendrogliomas, high-grade astrocytomas, and medulloblastomas [J].
Broderick, DK ;
Di, CH ;
Parrett, TJ ;
Samuels, YR ;
Cummins, JM ;
McLendon, RE ;
Fults, DW ;
Velculescu, VE ;
Bigner, DD ;
Yan, H .
CANCER RESEARCH, 2004, 64 (15) :5048-5050
[5]   Mutation of the PIK3CA gene in ovarian and breast cancer [J].
Campbell, IG ;
Russell, SE ;
Choong, DYH ;
Montgomery, KG ;
Ciavarella, ML ;
Hooi, CSF ;
Cristiano, BE ;
Pearson, RB ;
Phillips, WA .
CANCER RESEARCH, 2004, 64 (21) :7678-7681
[6]   Transformation of chicken cells by the gene encoding the catalytic subunit of PI 3-kinase [J].
Chang, HW ;
Aoki, M ;
Fruman, D ;
Auger, KR ;
Bellacosa, A ;
Tsichlis, PN ;
Cantley, LC ;
Roberts, TM ;
Vogt, PK .
SCIENCE, 1997, 276 (5320) :1848-1850
[7]   Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the philadelphia chromosome. [J].
Druker, BJ ;
Sawyers, CL ;
Kantarjian, H ;
Resta, DJ ;
Reese, SF ;
Ford, JM ;
Capdeville, R ;
Talpaz, M .
NEW ENGLAND JOURNAL OF MEDICINE, 2001, 344 (14) :1038-1042
[8]   Integrinαvβ3 requirement for sustained mitogen-activated protein kinase activity during angiogenesis [J].
Eliceiri, BP ;
Klemke, R ;
Strömblad, S ;
Cheresh, DA .
JOURNAL OF CELL BIOLOGY, 1998, 140 (05) :1255-1263
[9]   Phosphoinositide kinases [J].
Fruman, DA ;
Meyers, RE ;
Cantley, LC .
ANNUAL REVIEW OF BIOCHEMISTRY, 1998, 67 :481-507
[10]   Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor [J].
Guba, M ;
von Breitenbuch, P ;
Steinbauer, M ;
Koehl, G ;
Flegel, S ;
Hornung, M ;
Bruns, CJ ;
Zuelke, C ;
Farkas, S ;
Anthuber, M ;
Jauch, KW ;
Geissler, EK .
NATURE MEDICINE, 2002, 8 (02) :128-135