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.
Highlights
The liver is a common metastatic site for numerous cancers, with the most prominent source of hepatic metastases originating from colorectal and breast tumors [1]
We observed an increase in Claudin-2 levels when human (Figure 1A) and mouse (Figure 1B) breast cancer cells were individually treated with each Src Family Kinase (SFK) inhibitor
Using reporter assays and chromatin immunoprecipitation approaches, it has recently been shown that the EGFR-MEK-ERK1/2 pathway can regulate the transcription of CLDN2 in A549 lung adenocarcinoma cells [28]
Summary
The liver is a common metastatic site for numerous cancers, with the most prominent source of hepatic metastases originating from colorectal and breast tumors [1]. Cancer cells that arrive in the liver must contend with unique microenvironmental influences that differ markedly from the primary tumor These include interactions with specialized cell types within the liver such as sinusoidal endothelial cells, Kupffer cells, Hepatic stellate cells, Pit cells and hepatocytes. Coupled with these new cellular interactions, cancer cells encounter unique features of the liver architecture that together play significant roles in modulating the ability of cancer cells to seed, colonize and grow in this organ [3]. These parameters greatly influence the selection of cancer cells that are best suited to thrive in the liver
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