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. [Cancer Res 2009;69(15):6299-306]

The PI3 kinase/mTOR blocker NVP-BEZ235 overrides resistance against irreversible ErbB inhibitors in breast cancer cells

“…However, in this study, PIK3CA mutations [41] were found in both drug-sensitive and drug-resistant breast cancer cells ( 56] failed to demonstrate a correlation between the presence of PIK3CA mutations and expression of pAKT, nor did they provide evidence that such mutations shorten survival or elevate chemoresistance in breast tumor patients [55]. Consistently, recent evidence indicates that when PDK1, which is overexpressed in a large proportion of breast cancers [8], is activated by mutant PIK3CA, it phosphorylates SGK3 rather than AKT [56]. Therefore, PIK3CA mutations may at best contribute to drug-refractory AKT signaling and growth resistance, but are definitely not the sole causes for it.…”

“…All ErbB receptors except ErbB3 activate various downstream signaling molecules including the phosphatidylinositol 3-kinase (PI3K) and its downstream mediators AKT and mTOR, and the mitogen-activated protein kinase (MAPK) cascade proteins C-RAF, MEK, and ERK [7,8]. Both, the MAPK-and the PI3K signaling pathway, have been involved in resistance of tumor cells against ErbB-targeting drugs [9][10][11].…”

The PKCθ pathway participates in the aberrant accumulation of Fra-1 protein in invasive ER-negative breast cancer cells

“…34 Recently, the GCK-like kinase (MAP4K3) has been shown to directly phosphorylate PKCy on T538. 35 Although expression of GLK has not been studied in breast cancer, both LCK 36 and 3-phosphoinositide-dependent kinase 1 37 have been reported to be overexpressed, especially in ERÀ compared with ER þ tumours for the tyrosine kinase. (b) MCF7 cells were transiently transfected with 50 ng of the pIRES2 --EGFP vector expressing either wild-type Fra-1 (WT) or mutated Fra-1 in which serines 252 and 265 were replaced by alanine (S/A).…”

Comprehensive analysis of PTEN status in breast carcinomas

“…1,2 Activating mutations in PIK3CA, which encodes the PI3K catalytic subunit, have been reported in approximately a quarter of breast tumors 3 and copy number gain of this gene has been identified in 1-14% of breast cancers. [4][5][6] Approximately one fifth of breast cancers are described as having loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression (range 4-48%) [6][7][8][9][10][11][12][13][14][15] and epigenetic silencing of the PTEN gene through promoter hypermethylation has been reported in 34% 16 and 48% 17 of breast cancers. Loss of heterozygosity at the PTEN locus is observed in 40% of invasive breast carcinomas 18,19 but mutations in this gene have only been identified in 2-9% of breast cancers 3,7,[20][21][22] suggesting that PTEN haploinsufficiency may have tumorigenic consequences.…”