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Cooperation between Noncanonical Ras Network Mutations.

ABSTRACT: Cancer develops after the acquisition of a collection of mutations that together create the cancer phenotype. How collections of mutations work together within a cell and whether there is selection for certain combinations of mutations are not well understood. We investigated this problem with a mathematical model of the Ras signaling network, including a computational random mutagenesis. Modeling and subsequent experiments revealed that mutations of the tumor suppressor gene NF1 can amplify the effects of other Ras pathway mutations, including weakly activating, noncanonical Ras mutants. Furthermore, analyzing recently available, large, cancer genomic data sets uncovered increased co-occurrence of NF1 mutations with mutations in other Ras network genes. Overall, these data suggest that combinations of Ras pathway mutations could serve the role of cancer "driver." More generally, this work suggests that mutations that result in network instability may promote cancer in a manner analogous to genomic instability.

SUBMITTER: Stites EC

PROVIDER: S-EPMC4503519 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Cooperation between Noncanonical Ras Network Mutations.

Stites Edward C EC Trampont Paul C PC Haney Lisa B LB Walk Scott F SF Ravichandran Kodi S KS

Cell reports 20150115 3

Cancer develops after the acquisition of a collection of mutations that together create the cancer phenotype. How collections of mutations work together within a cell and whether there is selection for certain combinations of mutations are not well understood. We investigated this problem with a mathematical model of the Ras signaling network, including a computational random mutagenesis. Modeling and subsequent experiments revealed that mutations of the tumor suppressor gene NF1 can amplify the ...[more]

PMID: 25600866

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Project description:BackgroundRecent studies have implicated aberrant Notch signaling in breast cancers. Yet, relatively little is known about the pattern of expression of various components of the Notch pathway, or its mechanism of action. To better understand the role of the Notch pathway in breast cancer, we have undertaken a detailed expression analysis of various Notch receptors, their ligands, and downstream targets at different stages of breast cancer progression.ResultsWe report here that there is a general increase in the expression levels of Notch 1, 2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers, with simultaneous upregulation of multiple Notch receptors and ligands in a given cancer tissue. While Notch3 and Delta-like1 were undetectable in normal tissues, moderate to high expression was detected in several cancers. We detected the presence of active, cleaved Notch1, along with downstream targets of the Notch pathway, Hes1/Hes5, in approximately 75% of breast cancers, clearly indicating that in a large proportion of breast cancers Notch signaling is aberrantly activated. Furthermore, we detected cleaved Notch1 and Hes1/5 in early precursors of breast cancers - hyperplasia and ductal carcinoma in situ - suggesting that aberrant Notch activation may be an early event in breast cancer progression. Mechanistically, while constitutively active Notch1 alone failed to transform immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate transformation. This cooperation is reflected in vivo, as a subset of cleaved Notch positive tumors additionally expressed phopsho-Erk1/2 in the nuclei. Such cases exhibited high node positivity, suggesting that Notch-Ras cooperation may lead to poor prognosis.ConclusionsHigh level expression of Notch receptors and ligands, and its increased activation in several breast cancers and early precursors, places Notch signaling as a key player in breast cancer pathogenesis. Its cooperation with the Ras/MAPK pathway in transformation offers combined inhibition of the two pathways as a new modality for breast cancer treatment.

Dataset Information

Cooperation between Noncanonical Ras Network Mutations.

Publications

Cooperation between Noncanonical Ras Network Mutations.

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