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GEO help: Mouse over screen elements for information. |
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Status |
Public on Oct 01, 2022 |
Title |
Omics analyses of a somatic Trp53R245W/+ breast cancer model identify cooperating driver events activating PI3K/Akt/mTOR signaling |
Organism |
Mus musculus |
Experiment type |
Expression profiling by high throughput sequencing
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Summary |
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.
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Overall design |
Comparative gene expression profiling analysis of RNA-seq data for mouse breast tumors driven by somatic Trp53R245W and enriched epithelia isolated from mammary glands of mice in the same cohort
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Contributor(s) |
Yu X, Zhang Y, Xiong S, McDaniel J, Sun C, Gencel-Augusto J, Chachad D, Morrissey R, Rao X, Wang J, Lozano G |
Citation(s) |
36322759 |
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Submission date |
Jul 06, 2022 |
Last update date |
Dec 13, 2022 |
Contact name |
Khandan Keyomarsi |
E-mail(s) |
kkeyomar@mdanderson.org
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Organization name |
The University of Texas MD Anderson Cancer Center
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Department |
Experimental Radiation Onc
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Street address |
1515 Holcombe Blvd
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City |
Houston |
State/province |
TX |
ZIP/Postal code |
77030 |
Country |
USA |
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Platforms (2) |
GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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Samples (12)
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Relations |
BioProject |
PRJNA856307 |
Supplementary file |
Size |
Download |
File type/resource |
GSE207604_RAW.tar |
2.3 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
Raw data are available in SRA |
Processed data provided as supplementary file |
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