Abstract
Claudin-2 enhances breast cancer liver metastasis and promotes the development of colorectal cancers. The objective of our current study is to define the regulatory mechanisms controlling Claudin-2 expression in breast cancer cells. We evaluated the effect of several Src Family Kinase (SFK) inhibitors or knockdown of individual SFK members on Claudin-2 expression in breast cancer cells. We also assessed the potential effects of pan-SFK and SFK-selective inhibitors on the formation of breast cancer liver metastases. This study reveals that pan inhibition of SFK signaling pathways significantly elevated Claudin-2 expression levels in breast cancer cells. In addition, our data demonstrate that pan-SFK inhibitors can enhance breast cancer metastasis to the liver. Knockdown of individual SFK members reveals that loss of Yes or Fyn induces Claudin-2 expression; whereas, diminished Lyn levels impairs Claudin-2 expression in breast cancer cells. The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis. Our findings may have major clinical implications and advise against the treatment of breast cancer patients with broad-acting SFK inhibitors and support the use of Lyn-specific inhibitors.
Keywords:
Lyn; Src family kinase; breast cancer; claudins; liver metastasis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Apoptosis / drug effects
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Carcinoma / genetics
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Carcinoma / prevention & control
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Carcinoma / secondary*
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Cell Line, Tumor
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Claudins / biosynthesis*
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Claudins / genetics
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Dasatinib / pharmacology
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Dasatinib / therapeutic use
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Female
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Gene Expression Regulation, Neoplastic* / drug effects
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Humans
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Liver Neoplasms / prevention & control
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Liver Neoplasms / secondary*
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Mammary Neoplasms, Experimental / genetics
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Mammary Neoplasms, Experimental / pathology*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred NOD
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Mice, SCID
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Molecular Targeted Therapy*
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Neoplasm Proteins / antagonists & inhibitors
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Promoter Regions, Genetic
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Protein Kinase Inhibitors / pharmacology
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Protein Kinase Inhibitors / therapeutic use
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Proto-Oncogene Proteins c-fos / physiology
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Pyrimidines / pharmacology
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Pyrimidines / therapeutic use
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RNA Interference
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RNA, Messenger / biosynthesis
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RNA, Messenger / genetics
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RNA, Neoplasm / biosynthesis
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RNA, Neoplasm / genetics
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Signal Transduction
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Transcription Factor AP-1 / physiology
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Transcription, Genetic
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Triple Negative Breast Neoplasms / genetics
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Triple Negative Breast Neoplasms / pathology*
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src-Family Kinases / antagonists & inhibitors
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src-Family Kinases / physiology*
Substances
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AG 1879
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CLDN2 protein, human
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Claudins
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Neoplasm Proteins
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Protein Kinase Inhibitors
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Proto-Oncogene Proteins c-fos
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Pyrimidines
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RNA, Messenger
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RNA, Neoplasm
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Transcription Factor AP-1
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lyn protein-tyrosine kinase
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src-Family Kinases
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bafetinib
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Dasatinib