Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis

• Published in: Oncotarget 2015-04, Vol.6 (11), p.9476-9487
• Main Authors: Tabariès, Sébastien, Annis, Matthew G, Hsu, Brian E, Tam, Christine E, Savage, Paul, Park, Morag, Siegel, Peter M
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - drug effects; Carcinoma - genetics; Carcinoma - prevention & control; Carcinoma - secondary; Cell Line, Tumor; Claudins - biosynthesis; Claudins - genetics; Dasatinib - pharmacology; Dasatinib - therapeutic use; Female; Gene Expression Regulation, Neoplastic - drug effects; Humans; Liver Neoplasms - prevention & control; Liver Neoplasms - secondary; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - pathology; Mice; Mice, Inbred BALB C; Mice, Inbred NOD; Mice, SCID; Molecular Targeted Therapy; Neoplasm Proteins - antagonists & inhibitors; Neoplasm Proteins - biosynthesis; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Promoter Regions, Genetic; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-fos - physiology; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Research Paper; RNA Interference; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; RNA, Neoplasm - biosynthesis; RNA, Neoplasm - genetics; Signal Transduction; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - physiology; Transcription Factor AP-1 - physiology; Transcription, Genetic; Triple Negative Breast Neoplasms - genetics; Triple Negative Breast Neoplasms - pathology
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.3269

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.