title: Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis.
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.
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Tabariès
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Annis
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.
authors.forename: Brian E
authors.initials: BE
authors.lastname: Hsu
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Tam
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.
authors.forename: Paul
authors.initials: P
authors.lastname: Savage
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Oncology, McGill University, Montréal, Québec, Canada, H3A 1A3.
authors.forename: Morag
authors.initials: M
authors.lastname: Park
authors.affiliation: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3.|Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3A 1A3.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Siegel
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002277:Carcinoma / Q000235:genetics / Q000517:prevention & control / Q000556:secondary*; D045744:Cell Line, Tumor; D057167:Claudins / Q000096:biosynthesis* / Q000235:genetics; D000069439:Dasatinib / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016760:Proto-Oncogene Proteins c-fos / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D012334:RNA, Neoplasm / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000502:physiology; D014158:Transcription, Genetic; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: C412373:AG 1879; C491875:CLDN2 protein, human; D057167:Claudins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018808:Transcription Factor AP-1; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; C506918:bafetinib; D000069439:Dasatinib
keywords: Lyn; Src family kinase; breast cancer; claudins; liver metastasis
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