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Mutant SF3B1 promotes AKT and NF-kB driven mammary tumorigenesis

UID: 10795

Author(s): Bo, Liu* * MSK affiliated

Description
Summary from the GEO: "Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but also recurrent in epithelial malignancies such as breast cancer. Whereas hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to epithelial cancer development and progression is unknown. Here, we identify that SF3B1 mutations in mammary epithelial and breast cancer cells induce a recurrent pattern of aberrant splicing leading to activation of AKT and NF-kB, enhanced cell migration, and accelerated tumorigenesis. Transcriptomic analysis of human cancer specimens, MMTV-cre Sf3b1K700E/WT mice, and isogenic mutant cell lines identified hundreds of aberrant 3’ splice sites induced by mutant SF3B1, a portion of which were breast-specific. Across mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the aberrant branchpoint) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-kB. Coordinate activation of NF-kB and AKT signaling was observed in the knock-in models, leading to accelerated cell migration and tumor development in combination with mutant PIK3CA but also hypersensitizing cells to AKT kinase inhibitors. These data identify mutations in SF3B1 as drivers of breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them."

Overall design: "23 samples, including 11 mouse and 12 human samples with varying SF3B1 status"
Subject of Study
Homo sapiens
Mus musculus
Subject(s)
Breast Neoplasms
NF-kappa B
Phosphoproteins
Proto-Oncogene Proteins c-akt
RNA Splicing Factors
OncoTree Cancer Type(s)
Breast
Access via GEO

TAB files of expression profiling by high throughput sequencing
Accession #: GSE145471

Access via SRA

RNA sequencing of 23 samples.
Accession #: SRP249914

Access via BioProject

Additional information about the overall inititative.
Accession #: PRJNA607270

Access Restrictions
Free to All
Access Instructions
The NCBI Gene Expression Omnibus, SRA, and BioProject databases provide open access to these files. The SRA Run Selector link at the bottom of the page is a processing tool for raw data.
Associated Publications
Liu B, Liu Z, Chen S, et al. Mutant SF3B1 promotes AKT- and NF-κB-driven mammary tumorigenesis. Journal of Clinical Investigation. 2021; 131(1):e138315.
Data Type
Genomic
Equipment Used
Illumina HiSeq 2500

High throughput sequencing system

Software Used
SRA Toolkit

The NCBI SRA Toolkit enables reading ("dumping") of sequencing files from the SRA database and writing ("loading") files into the .sra format.

Dataset Format(s)
SRA, TAR, TAB
Data Tool(s)
RNA Seq
Dataset Size
79.4 MB (TAR of TAB), 301.2 (SRA)
Data Catalog Record Updated
2023-12-07