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Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis
Sébastien Tabariès1,2, Matthew G Annis1,2, Brian E Hsu1,2
1Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3.
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.
Insights
Broad Src Family Kinase (SFK) inhibition increases Claudin-2 and breast cancer liver metastasis. Lyn-specific inhibitors, like Bafetinib, reduce Claudin-2 and metastasis, suggesting targeted therapy potential.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Claudin-2 is implicated in breast cancer liver metastasis and colorectal cancer development.
- Understanding Claudin-2 regulation is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To elucidate the regulatory mechanisms of Claudin-2 expression in breast cancer cells.
- To investigate the impact of Src Family Kinase (SFK) signaling on Claudin-2 and liver metastasis.
Main Methods:
- Evaluating the effects of SFK inhibitors and SFK member knockdown on Claudin-2 expression.
- Assessing the influence of pan-SFK and selective SFK inhibitors on breast cancer liver metastasis formation.
- Utilizing the Lyn-selective kinase inhibitor, Bafetinib (INNO-406).
Main Results:
- Pan-SFK inhibition significantly elevated Claudin-2 expression and enhanced liver metastasis.
- Knockdown of Yes or Fyn induced Claudin-2, while diminished Lyn impaired its expression.
- Bafetinib reduced Claudin-2 expression and suppressed liver metastasis.
Conclusions:
- Broad-acting SFK inhibitors may promote breast cancer liver metastasis and should be used cautiously.
- Targeting Lyn with specific inhibitors like Bafetinib shows promise in reducing Claudin-2 expression and metastasis.
- Findings support the use of Lyn-specific inhibitors for breast cancer treatment to prevent liver metastasis.
