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Omics analyses of a somatic Trp53R245W/+ breast cancer model identify cooperating driver events activating PI3K/Akt/mTOR signaling

ABSTRACT: Alterations of the tumor suppressor TP53, one of the most common events in cancer, alone are insufficient for tumor development but serve as drivers of transformation. We sought to identify cooperating events through genomic analyses of a novel somatic Trp53R245W mouse model (equivalent to the TP53R248W hot spot mutation in human cancers) that recapitulates metastatic breast cancer development. We identified cooperating lesions similar to those found in human breast cancers. Moreover, we identified activation of the Pi3k/Akt/mTOR pathway in most tumors via mutations in Pten, Erbb2, Kras and/or a recurrent Pip5k1c mutation that stabilizes the Pip5k1c protein to activate Pi3k/Akt/mTOR signaling. Another PIP5K1C family member, PIP5K1A, is co-amplified with PI4KB in 18% of human breast cancer patients and both encode kinases that are responsible for production of the PI3K substrate, phosphatidylinositol 4,5-bisphosphate. Thus, the TP53R248W mutation and PI3K/Akt/mTOR signaling are major cooperative events driving breast cancer development. Additionally, we demonstrated that the upregulation of oxidative phosphorylation by Pi3k/Akt/mTOR signaling is a vulnerability in murine as well as human breast cancer cell lines. These findings advance our understanding of mutant p53-driven breast tumors and expand testable targets for breast cancer treatment.

ORGANISM(S): Mus musculus

PROVIDER: GSE207604 | GEO | 2022/10/01

REPOSITORIES: GEO

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Project description:Mosca2012 - Central Carbon Metabolism Regulated by AKT The role of the PI3K/Akt/PKB signalling pathway in oncogenesis has been extensively investigated and altered expression or mutations of many components of this pathway have been implicated in human cancers. Indeed, expression of constitutively active forms of Akt/PKB can prevent cell death upon growth factor withdrawal. PI3K/Akt/mTOR-mediated survival relies on a profound metabolic adaptation, including aerobic glycolysis. Here, the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis has been modelled, considering two states - high and low PI3K/Akt/mTOR activity. The high PI3K/Akt/mTOR activity represents cancer cell line where PI3K/Akt/mTOR promotes a high rate of glucose metabolism (condition H) and the low PI3K/Akt/mTOR activity is characterised by a lower glycolytic rate due to a reduced PI3K/Akt/mTOR signal (condition L). This model corresponds to the high PI3K/Akt/mTOR signal (condition H). This model is described in the article: Computational Modelling of the Metabolic States Regulated by the Kinase Akt. Mosca E, Alfieri R, Maj C, Bevilacqua A, Canti G, Milanesi L. Frontiers in Systems Biology. 2012 Oct 13 Abstract: Signal transduction pathways and gene regulation determine a major reorganization of metabolic activities in order to support cell proliferation. Protein Kinase B (PKB), also known as Akt, participates in the PI3K/Akt/mTOR pathway, a master regulator of aerobic glycolysis and cellular biosynthesis, two activities shown by both normal and cancer proliferating cells. Not surprisingly considering its relevance for cellular metabolism, Akt/PKB is often found hyperactive in cancer cells. In the last decade, many efforts have been made to improve the understanding of the control of glucose metabolism and the identification of a therapeutic window between proliferating cancer cells and proliferating normal cells. In this context, we have modelled the link between the PI3K/Akt/mTOR pathway, glycolysis, lactic acid production and nucleotide biosynthesis. We used a computational model in order to compare two metabolic states generated by the specific variation of the metabolic fluxes regulated by the activity of the PI3K/Akt/mTOR pathway. One of the two states represented the metabolism of a growing cancer cell characterised by aerobic glycolysis and cellular biosynthesis, while the other state represented the same metabolic network with a reduced glycolytic rate and a higher mitochondrial pyruvate metabolism, as reported in literature in relation to the activity of the PI3K/Akt/mTOR. Some steps that link glycolysis and pentose phosphate pathway revealed their importance for controlling the dynamics of cancer glucose metabolism. This model is hosted on BioModels Database and identified by: MODEL1210150000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Omics analyses of a somatic Trp53R245W/+ breast cancer model identify cooperating driver events activating PI3K/Akt/mTOR signaling

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