title: 3-Phosphoinositide-dependent kinase 1 potentiates upstream lesions on the phosphatidylinositol 3-kinase pathway in breast carcinoma.
abstract: 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 (PIP(3)). 3-Phosphoinositide-dependent kinase 1 (PDK1) is the first node of the PI3K signal output and is required for activation of AKT. PIP(3) 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 AKT, 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.
authors: Department of Medicine and Pathology, Herbert Irving Comprehensive Cancer Center, Institute for Cancer Genetics, College of Physicians and Surgeons, Columbia University, New York, New York 10032, USA.
authors: Matthew
authors: M
authors: Maurer
authors: Tao
authors: T
authors: Su
authors: Lao H
authors: LH
authors: Saal
authors: Susan
authors: S
authors: Koujak
authors: Benjamin D
authors: BD
authors: Hopkins
authors: Christina R
authors: CR
authors: Barkley
authors: Jiaping
authors: J
authors: Wu
authors: Subhadra
authors: S
authors: Nandula
authors: Bhaskar
authors: B
authors: Dutta
authors: Yuli
authors: Y
authors: Xie
authors: Y Rebecca
authors: YR
authors: Chin
authors: Da-In
authors: DI
authors: Kim
authors: Jennifer S
authors: JS
authors: Ferris
authors: Sofia K
authors: SK
authors: Gruvberger-Saal
authors: Mervi
authors: M
authors: Laakso
authors: Xiaomei
authors: X
authors: Wang
authors: Lorenzo
authors: L
authors: Memeo
authors: Albert
authors: A
authors: Rojtman
authors: Tulio
authors: T
authors: Matos
authors: Jennifer S
authors: JS
authors: Yu
authors: Carlos
authors: C
authors: Cordon-Cardo
authors: Jorma
authors: J
authors: Isola
authors: Mary Beth
authors: MB
authors: Terry
authors: Alex
authors: A
authors: Toker
authors: Gordon B
authors: GB
authors: Mills
authors: Jean J
authors: JJ
authors: Zhao
authors: Vundavalli V V S
authors: VV
authors: Murty
authors: Hanina
authors: H
authors: Hibshoosh
authors: Ramon
authors: R
authors: Parsons
mesh_terms: D064413:3-Phosphoinositide-Dependent Protein Kinases; D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005260:Female; D018628:Gene Dosage; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D064413:3-Phosphoinositide-Dependent Protein Kinases; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human; C578562:PDPK1 protein, human; C578564:Pdpk1 protein, mouse