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

Abstract

// Sébastien Tabariès 1, 2 , Matthew G. Annis 1, 2 , Brian E. Hsu 1, 2 , Christine E. Tam 1, 2 , Paul Savage 1, 2 , Morag Park 1, 2, 3, 4 , Peter M. Siegel 1, 2, 3 1 Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3 2 Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3 3 Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3A 1A3 4 Department of Oncology, McGill University, Montréal, Québec, Canada, H3A 1A3 Correspondence to: Peter M. Siegel, e-mail: peter.siegel@mcgill.ca Keywords: breast cancer, liver metastasis, claudins, Src family kinase, Lyn Received: January 26, 2015      Accepted: January 31, 2015      Published: March 25, 2015 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.