title: Oncogenic PI3K mutations lead to NF-κB-dependent cytokine expression following growth factor deprivation.
abstract: The phosphoinositide 3-kinase (PI3K) pathway is one of the most commonly misregulated signaling pathways in human cancers, but its impact on the tumor microenvironment has not been considered as deeply as its autonomous impact on tumor cells. In this study, we show that NF-κB is activated by the two most common PI3K mutations, PIK3CA E545K and H1047R. We found that markers of NF-κB are most strongly upregulated under conditions of growth factor deprivation. Gene expression analysis conducted on cells deprived of growth factors identified the repertoire of genes altered by oncogenic PI3K mutations following growth factor deprivation. This gene set most closely correlated with gene signatures from claudin-low and basal-like breast tumors, subtypes frequently exhibiting constitutive PI3K/Akt activity. An NF-κB-dependent subset of genes driven by oncogenic PI3K mutations was also identified that encoded primarily secreted proteins, suggesting a paracrine role for this gene set. Interestingly, while NF-κB activated by oncogenes such as Ras and EGF receptor leads to cell-autonomous effects, abrogating NF-κB in PI3K-transformed cells did not decrease proliferation or induce apoptosis. However, conditioned media from PI3K mutant-expressing cells led to increased STAT3 activation in recipient THP-1 monocytes or normal epithelial cells in a NF-κB and interleukin-6-dependent manner. Together, our findings describe a PI3K-driven, NF-κB-dependent transcriptional profile that may play a critical role in promoting a microenvironment amenable to tumor progression. These data also indicate that NF-κB plays diverse roles downstream from different oncogenic signaling pathways.
authors.affiliation: Lineberger Comprehensive Cancer Center, Department of Biology, University of North Carolina at Chapel Hill, North Carolina 27599, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Hutti
authors.forename: Adam D
authors.initials: AD
authors.lastname: Pfefferle
authors.forename: Sean C
authors.initials: SC
authors.lastname: Russell
authors.forename: Mayukh
authors.initials: M
authors.lastname: Sircar
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
authors.forename: Albert S
authors.initials: AS
authors.lastname: Baldwin
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D016207:Cytokines; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases