ResearchIn-Press PreviewOncology Open Access | 10.1172/jci.insight.171705
1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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1UNC Lineberger Comprehensive Cancer, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
2Division of Surgical Oncology, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
3UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
4NOMIS Center for Immunobiology and Microbial Pathogenesis, The Salk Institute, La Jolla, United States of America
5Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, United States of America
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Published October 17, 2024 - More info
Despite proven therapy options for estrogen receptor (ER)-positive breast tumors, a substantial number of ER+ cancer patients exhibit relapse with associated metastasis. Loss of expression of RasGAPs leads to poor outcomes in several cancers, including breast cancer. Mining the TCGA breast cancer RNA-sequencing dataset revealed that low expression of the RasGAP DAB2IP was associated with a significant decrease in relapse-free survival in Luminal A breast cancer patients. Immunostaining demonstrated that DAB2IP loss occurred in grade 2 tumors and higher. Consistent with this, genes upregulated in DAB2IP-low Luminal A tumors were shared with more aggressive tumor subtypes and were associated with proliferation, metastasis, and altered ER signaling. Low DAB2IP expression in ER+ breast cancer cells was associated with increased proliferation, enhanced stemness phenotypes, and activation of IKK, the upstream regulator of the transcription factor NF-kB. Integrating cell-based ChIP-sequencing with motif analysis and TCGA RNA-seq data, we identified a set of candidate NF-kB target genes upregulated with loss of DAB2IP linked with several oncogenic phenotypes, including altered RNA processing. This study provides insight into mechanisms associated with aggressiveness and recurrence within a subset of the typically less aggressive Luminal A breast cancer intrinsic subtype.
View Unedited blot and gel images
View Supplementary Figure S8. Effect of loss of DAB2IP on NF-kB target gene BIRC5 in T47D cells.
View Supplementary Table S1. Proliferation score and Risk of Recurrence (ROR) scores.
View Supplementary Table S2. Resultant gene list for all enrichment analysis
View Supplementary Table S5. Up- and down-regulated NF-κB genes in DAB2IP-low Luminal A tumors.