Abstract
Recent studies suggest that BET inhibitors are effective anti-cancer therapeutics. Here we show that BET inhibitors are effective against murine primary mammary tumors, but not pulmonary metastases. BRD4, a target of BET inhibitors, encodes two isoforms with opposite effects on tumor progression. To gain insights into why BET inhibition was ineffective against metastases the pro-metastatic short isoform of BRD4 was characterized using mass spectrometry and cellular fractionation. Our data show that the pro-metastatic short isoform interacts with the LINC complex and the metastasis-associated proteins RRP1B and SIPA1 at the inner face of the nuclear membrane. Furthermore, histone binding arrays revealed that the short isoform has a broader acetylated histone binding pattern relative to the long isoform. These differential biochemical and nuclear localization properties revealed in our study provide novel insights into the opposing roles of BRD4 isoforms in metastatic breast cancer progression.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Apoptosis Regulatory Proteins / metabolism*
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Cell Cycle Proteins
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Cell Line, Tumor
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Cell Nucleus / metabolism
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Chromosomal Proteins, Non-Histone / metabolism*
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Disease Models, Animal
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Female
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GTPase-Activating Proteins / metabolism*
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Histones / metabolism
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Humans
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Proteins / metabolism
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Mice
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Microtubule-Associated Proteins / metabolism
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N-Terminal Acetyltransferase E / metabolism
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N-Terminal Acetyltransferases
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Neoplasm Metastasis
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Neoplasms / metabolism
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Neoplasms / pathology
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Nuclear Envelope / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein Binding
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Protein Isoforms
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Protein Transport
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Tumor Burden / drug effects
Substances
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Apoptosis Regulatory Proteins
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BRD4 protein, human
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Cell Cycle Proteins
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Chromosomal Proteins, Non-Histone
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GSK1210151A
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GTPase-Activating Proteins
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Heterocyclic Compounds, 4 or More Rings
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Histones
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Microtubule-Associated Proteins
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Nuclear Proteins
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Protein Isoforms
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RRP1B protein, human
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SIPA1 protein, human
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SUN1 protein, human
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SUN2 protein, human
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Transcription Factors
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N-Terminal Acetyltransferase E
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N-Terminal Acetyltransferases
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NAT10 protein, human