Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis
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Sébastien Tabariès1,2, Matthew G. Annis1,2, Brian E. Hsu1,2, Christine E. Tam1,2, Paul Savage1,2, Morag Park1,2,3,4, Peter M. Siegel1,2,3
1Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3
2Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3
3Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3A 1A3
4Department of Oncology, McGill University, Montréal, Québec, Canada, H3A 1A3
Peter M. Siegel, e-mail: [email protected]
Keywords: breast cancer, liver metastasis, claudins, Src family kinase, Lyn
Received: January 26, 2015 Accepted: January 31, 2015 Published: March 25, 2015
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.
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