Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer

Oncotarget
Alvaro Avivar-ValderasFrancisco Cruzalegui

Abstract

The PI3Kα signaling pathway is frequently hyper-activated in breast cancer (BrCa), as a result of mutations/amplifications in oncogenes (e.g. HER2), decreased function in tumor suppressors (e.g. PTEN) or activating mutations in key components of the pathway. In particular, activating mutations of PIK3CA (~45%) are frequently found in luminal A BrCa samples. Genomic studies have uncovered inactivating mutations in MAP3K1 (13-20%) and MAP2K4 (~8%), two upstream kinases of the JNK apoptotic pathway in luminal A BrCa samples. Further, simultaneous mutation of PIK3CA and MAP3K1 are found in ~11% of mutant PIK3CA tumors. How these two alterations may cooperate to elicit tumorigenesis and impact the sensitivity to PI3K and AKT inhibitors is currently unknown. Using CRISPR gene editing we have genetically disrupted MAP3K1 expression in mutant PIK3CA cell lines to specifically create in vitro models reflecting the mutational status of PIK3CA and MAP3K1 in BrCa patients. MAP3K1 deficient cell lines exhibited ~2.4-fold increased proliferation rate and decreased sensitivity to PI3Kα/δ(AZD8835) and AKT (AZD5363) inhibitors (~2.61 and ~5.23-fold IC50 increases, respectively) compared with parental control cell lines. In addition, mechanistic...Continue Reading

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Citations

Jan 23, 2019·Daru : Journal of Faculty of Pharmacy, Tehran University of Medical Sciences·Ali SaberHidde J Haisma
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Nov 10, 2020··Nazia FatimaLuis Rueda

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Methods Mentioned

BETA
pull-downs
xenograft
xenografts
Protein Assay
immunoprecipitation
PCR

Software Mentioned

HALO
CRISPResso
LAS X
GraphPad
ImageJ
SPOT
GraphPad Prism
Leica

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