Abstract
Metastasis is the major cause of cancer mortality. A more thorough understanding of the mechanisms driving this complex multistep process will aid in the identification and characterization of therapeutically targetable genetic drivers of disease progression. We demonstrate that KLF6-SV1, an oncogenic splice variant of the KLF6 tumor suppressor gene, is associated with increased metastatic potential and poor survival in a cohort of 671 lymph node-negative breast cancer patients. KLF6-SV1 overexpression in mammary epithelial cell lines resulted in an epithelial-to-mesenchymal-like transition and drove aggressive multiorgan metastatic disease in multiple in vivo models. Additionally, KLF6-SV1 loss-of-function studies demonstrated reversion to an epithelial and less invasive phenotype. Combined, these findings implicate KLF6-SV1 as a key driver of breast cancer metastasis that distinguishes between indolent and lethal early-stage disease and provides a potential therapeutic target for invasive breast cancer.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Aged
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Alternative Splicing / genetics*
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Animals
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Breast Neoplasms / genetics*
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Breast Neoplasms / pathology*
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Cell Movement
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Cell Proliferation
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Cell Survival
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Disease Progression
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Epithelial-Mesenchymal Transition / genetics
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Female
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Gene Expression Regulation, Neoplastic
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Humans
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors / genetics*
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Kruppel-Like Transcription Factors / metabolism
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Mice
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Middle Aged
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Multivariate Analysis
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Neoplasm Invasiveness
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Neoplasm Metastasis / genetics
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Nuclear Proteins
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Phenotype
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Prognosis
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Proportional Hazards Models
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Survival Analysis
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Twist-Related Protein 1
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Xenograft Model Antitumor Assays
Substances
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KLF6 protein, human
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Kruppel-Like Factor 6
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Kruppel-Like Transcription Factors
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Nuclear Proteins
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Proto-Oncogene Proteins
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RNA, Messenger
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TWIST1 protein, human
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Twist-Related Protein 1