期刊
ONCOTARGET
卷 6, 期 11, 页码 9476-9487出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.3269
关键词
breast cancer; liver metastasis; claudins; Src family kinase; Lyn
资金
- Terry Fox Foundation [17003]
- CIHR operating grant [MOP 136907]
- McGill Integrated Cancer Research Training Program
- CIHR MD/Ph.D. studentship
- CIHR/McGill System Biology Training Program
- Fonds de recherche en sante du Quebec (FRSQ)
- McGill University William Dawson Scholar
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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