Mutant SF3B1 promotes AKT- and NF-κB–driven mammary tumorigenesis
Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although hotspot mutations in SF3B1 alter hematopoietic differentiation, whether SF3B1 mutations contribute to ep...
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| Published in: | The Journal of clinical investigation Vol. 131; no. 1 |
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| Main Authors: | , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
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American Society for Clinical Investigation
04.01.2021
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| ISSN: | 0021-9738, 1558-8238, 1558-8238 |
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| Abstract | Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although 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-κB, 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 (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-κB. Coordinate activation of NF-κB and AKT signaling was observed in the knockin 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 hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them. |
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| AbstractList | Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although 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-κB, 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 (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-κB. Coordinate activation of NF-κB and AKT signaling was observed in the knockin 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 hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them.Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although 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-κB, 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 (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-κB. Coordinate activation of NF-κB and AKT signaling was observed in the knockin 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 hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them. Mutations in the core RNA splicing factor SF3B1 are prevalent in leukemias and uveal melanoma, but hotspot SF3B1 mutations are also seen in epithelial malignancies such as breast cancer. Although 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-κB, 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 (3'ss) induced by mutant SF3B1. Consistently between mouse and human tumors, mutant SF3B1 promoted aberrant splicing (dependent on aberrant branchpoints as well as pyrimidines downstream of the cryptic 3'ss) and consequent suppression of PPP2R5A and MAP3K7, critical negative regulators of AKT and NF-κB. Coordinate activation of NF-κB and AKT signaling was observed in the knockin 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 hotspot mutations in SF3B1 as an important contributor to breast tumorigenesis and reveal unique vulnerabilities in cancers harboring them. |
| Author | Reis-Filho, Jorge S. Liu, Zhaoqi Durham, Benjamin H. Abdel-Wahab, Omar Chen, Sisi Liu, Bo Ki, Michelle de Stanchina, Elisa Sun, Yiwei Chang, Qing Chandarlapaty, Sarat Rabadan, Raul Erickson, Caroline |
| AuthorAffiliation | 5 Department of Systems Biology and Department of Biomedical Informatics, Columbia University, New York, New York, USA 8 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA 2 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China 3 China National Center for Bioinformation, Beijing, China 6 Department of Pathology 1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA 9 Weill-Cornell Medicine, New York, New York, USA 7 Antitumor Assessment Core and Molecular Pharmacology Department, and 10 Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA 4 Program for Mathematical Genomics |
| AuthorAffiliation_xml | – name: 1 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA – name: 2 Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China – name: 8 Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA – name: 9 Weill-Cornell Medicine, New York, New York, USA – name: 7 Antitumor Assessment Core and Molecular Pharmacology Department, and – name: 6 Department of Pathology – name: 3 China National Center for Bioinformation, Beijing, China – name: 5 Department of Systems Biology and Department of Biomedical Informatics, Columbia University, New York, New York, USA – name: 10 Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA – name: 4 Program for Mathematical Genomics |
| Author_xml | – sequence: 1 givenname: Bo surname: Liu fullname: Liu, Bo – sequence: 2 givenname: Zhaoqi surname: Liu fullname: Liu, Zhaoqi – sequence: 3 givenname: Sisi surname: Chen fullname: Chen, Sisi – sequence: 4 givenname: Michelle surname: Ki fullname: Ki, Michelle – sequence: 5 givenname: Caroline surname: Erickson fullname: Erickson, Caroline – sequence: 6 givenname: Jorge S. surname: Reis-Filho fullname: Reis-Filho, Jorge S. – sequence: 7 givenname: Benjamin H. orcidid: 0000-0001-8090-5448 surname: Durham fullname: Durham, Benjamin H. – sequence: 8 givenname: Qing surname: Chang fullname: Chang, Qing – sequence: 9 givenname: Elisa orcidid: 0000-0002-3873-315X surname: de Stanchina fullname: de Stanchina, Elisa – sequence: 10 givenname: Yiwei orcidid: 0000-0002-5974-6232 surname: Sun fullname: Sun, Yiwei – sequence: 11 givenname: Raul orcidid: 0000-0001-7946-9255 surname: Rabadan fullname: Rabadan, Raul – sequence: 12 givenname: Omar orcidid: 0000-0002-3907-6171 surname: Abdel-Wahab fullname: Abdel-Wahab, Omar – sequence: 13 givenname: Sarat orcidid: 0000-0003-4532-8053 surname: Chandarlapaty fullname: Chandarlapaty, Sarat |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33031100$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Animals Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Carcinogenesis - genetics Carcinogenesis - metabolism Carcinogenesis - pathology Female Humans Mammary Neoplasms, Animal - genetics Mammary Neoplasms, Animal - metabolism Mammary Neoplasms, Animal - pathology Mice Mice, Transgenic Mutation NF-kappa B - genetics NF-kappa B - metabolism Phosphoproteins - genetics Phosphoproteins - metabolism Proto-Oncogene Proteins c-akt - genetics Proto-Oncogene Proteins c-akt - metabolism RNA Splicing Factors - genetics RNA Splicing Factors - metabolism |
| Title | Mutant SF3B1 promotes AKT- and NF-κB–driven mammary tumorigenesis |
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