共 49 条
3-Phosphoinositide-Dependent Kinase 1 Potentiates Upstream Lesions on the Phosphatidylinositol 3-Kinase Pathway in Breast Carcinoma
被引:113
作者:
Maurer, Matthew
[2
,4
]
Su, Tao
[4
]
Saal, Lao H.
[1
]
Koujak, Susan
[1
]
Hopkins, Benjamin D.
[1
]
Barkley, Christina R.
[6
,7
]
Wu, Jiaping
[6
]
Nandula, Subhadra
[3
]
Dutta, Bhaskar
[9
]
Xie, Yuli
[2
]
Chin, Y. Rebecca
[8
]
Kim, Da-In
[1
]
Ferris, Jennifer S.
[5
]
Gruvberger-Saal, Sofia K.
[1
]
Laakso, Mervi
[10
,11
,12
]
Wang, Xiaomei
[4
]
Memeo, Lorenzo
[13
]
Rojtman, Albert
[3
]
Matos, Tulio
[3
]
Yu, Jennifer S.
[1
,3
]
Cordon-Cardo, Carlos
[3
,4
]
Isola, Jorma
[11
,12
]
Terry, Mary Beth
[5
]
Toker, Alex
[8
]
Mills, Gordon B.
[9
]
Zhao, Jean J.
[6
]
Murty, Vundavalli V. V. S.
[3
,4
]
Hibshoosh, Hanina
[3
,4
]
Parsons, Ramon
[1
,2
,3
,4
]
机构:
[1] Columbia Univ, Inst Canc Genet, Coll Phys & Surg, New York, NY 10032 USA
[2] Columbia Univ, Dept Med, New York, NY 10032 USA
[3] Columbia Univ, Dept Pathol, New York, NY 10032 USA
[4] Columbia Univ, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA
[5] Columbia Univ, Dept Epidemiol, Mailman Sch Publ Hlth, New York, NY 10032 USA
[6] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA
[7] Harvard Univ, Sch Med, Dept Surg, Brigham & Womens Hosp, Boston, MA 02115 USA
[8] Harvard Univ, Sch Med, Dept Pathol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA
[9] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA
[10] Seinajoki Cent Hosp, Seinajoki, Finland
[11] Univ Tampere, Inst Med Technol, FIN-33101 Tampere, Finland
[12] Tampere Univ Hosp, Tampere, Finland
[13] Mediterranean Inst Oncol, Pathol Unit, Catania, Italy
关键词:
REGULATING CELL-MIGRATION;
PROTEIN-KINASE;
PIK3CA MUTATIONS;
PDK1;
ACTIVATION;
CANCER;
PTEN;
ONCOGENE;
AMPLIFICATION;
AKT1;
D O I:
10.1158/0008-5472.CAN-09-0820
中图分类号:
R73 [肿瘤学];
学科分类号:
100214 ;
摘要:
Lesions of ERBB2, PTEN, and PIK3CA activate the phosphatidylinositol 3-kinase (PI3K) pathway during cancer development by increasing levels of phosphatidylinositol-3,4,5-triphosphate (PIP3). 3-Phosphoinositide-dependent kinase 1 (PDK1) is the first node of the PI3K signal output and is required for activation of AKT. PIP3 recruits PDK1 and AKT to the cell membrane through interactions with their pleckstrin homology domains, allowing PDK1 to activate AKT by phosphorylating it at residue threonine-308. We show that total PDK1 protein and mRNA were overexpressed in a majority of human breast cancers and that 21% of tumors had five or more copies of the gene encoding PDK1, PDPK1. We found that increased PDPK1 copy number was associated with upstream pathway lesions (ERBB2 amplification, PTEN loss, or PIK3CA mutation), as well as patient survival. Examination of an independent set of breast cancers and tumor cell lines derived from multiple forms of human cancers also found increased PDK1 protein levels associated with such upstream pathway lesions. In human mammary cells, PDK1 enhanced the ability of upstream lesions to signal to ART, stimulate cell growth and migration, and rendered cells more resistant to PDK1 and PI3K inhibition. After orthotopic transplantation, PDK1 overexpression was not oncogenic but dramatically enhanced the ability of ERBB2 to form tumors. Our studies argue that PDK1 overexpression and increased PDPK1 copy number are common occurrences in cancer that potentiate the oncogenic effect of upstream lesions on the PI3K pathway. Therefore, we conclude that alteration of PDK1 is a critical component of oncogenic PI3K signaling in breast cancer. [Cancer Res 2009;69(15):6299-306]
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页码:6299 / 6306
页数:8
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