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AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

ABSTRACT: Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth. Instead, these cells retain robust PDK1 activation and membrane localization and exhibit dependency on the PDK1 substrate SGK3. SGK3 undergoes PI3K- and PDK1-dependent activation in PIK3CA mutant cancer cells. Thus, PI3K may promote cancer through both AKT-dependent and AKT-independent mechanisms. Knowledge of differential PI3K/PDK1 signaling could inform rational therapeutics in cancers harboring PIK3CA mutations.

SUBMITTER: Vasudevan KM

PROVIDER: S-EPMC2752826 | biostudies-literature | 2009 Jul

REPOSITORIES: biostudies-literature

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AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

Vasudevan Krishna M KM Barbie David A DA Davies Michael A MA Rabinovsky Rosalia R McNear Chontelle J CJ Kim Jessica J JJ Hennessy Bryan T BT Tseng Hsiuyi H Pochanard Panisa P Kim So Young SY Dunn Ian F IF Schinzel Anna C AC Sandy Peter P Hoersch Sebastian S Sheng Qing Q Gupta Piyush B PB Boehm Jesse S JS Reiling Jan H JH Silver Serena S Lu Yiling Y Stemke-Hale Katherine K Dutta Bhaskar B Joy Corwin C Sahin Aysegul A AA Gonzalez-Angulo Ana Maria AM Lluch Ana A Rameh Lucia E LE Jacks Tyler T Root David E DE Lander Eric S ES Mills Gordon B GB Hahn William C WC Sellers William R WR Garraway Levi A LA

Cancer cell 20090701 1

Dysregulation of the phosphatidylinositol 3-kinase (PI3K) signaling pathway occurs frequently in human cancer. PTEN tumor suppressor or PIK3CA oncogene mutations both direct PI3K-dependent tumorigenesis largely through activation of the AKT/PKB kinase. However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent ...[more]

PMID: 19573809

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Project description:Background: PIK3CA mutations are observed in >30% of breast cancers, which are more common in estrogen receptor (ERÎ±)-positive breast cancer compared with ERÎ±-negative breast cancer. AKT1, 2, and 3 isoforms, major isoforms downstream of PI3K, modulate ERÎ± activity. It is unknown whether PIK3CA mutation leads to preferential activation of specific AKT isoforms with an ability to modulate ERÎ± function. Methods: Gene expression arrays were performed on parental, AKT1 knockdown or AKT2 knockdown MCF-7 breast cancer cells with or without estradiol treatment for three hours. Results: AKT1 had a dominant role in ERÎ±:estradiol-dependent gene expression and proliferation. We have identified a unique gene expression signature that is dependent on ERÎ±, estradiol, AKT1 and the pioneer factor FOXA1. Overexpression of this signature was associated with better outcome in patients with ERÎ±-positive breast cancer. In contrast, AKT2 controlled global gene expression. Cells were maintained in phenol red free MEM with 5% charcoal dextran treated fetal calf serum for four days and then treated with ethanol or 0.1 nM estradiol for three hours. RNA was prepared using RNeasy kit (Qiagen, Valencia, CA, USA) Microarray with biological triplicates was performed using Illumina HumanHT-12 V4 expression beadchip. Genes that showed statistically insignificant signals in majority of samples were removed from the microarray data, and only those probes that showed statistically significant signal in at least half of samples of at least one group were retained. The probe level data was then collapsed to gene level data by retaining only the probes, which showed a maximal coefficient of variation across all samples. The data was imported into partek genomics suite for differential expression analysis. ANOVA analysis was performed to identify genes differentially expressed between AKT1KD vs. pLKO, AKT2KD vs. pLKO, and AKT1KD vs. AKT2KD groups. Stratagene Universal Human Reference RNA (Illumina Catalog # 740000) was used as quality control specimen

Dataset Information

AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

Publications

AKT-independent signaling downstream of oncogenic PIK3CA mutations in human cancer.

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