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

Tabariès S, Annis MG, Hsu BE, Tam CE, Savage P, Park M, Siegel PM - Oncotarget (2015)

Bottom Line: 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.The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis.

View Article: PubMed Central - PubMed

Affiliation: Goodman 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.

No MeSH data available.


Related in: MedlinePlus

Dasatinib treatment increases, while Bafetinib treatment lowers, Claudin-2 levels in breast cancer patient derived xenograft explantsImmunoblot analysis of Claudin-2 expression in GCRC1735 (A) or HCI010 (B) explants derived from triple negative breast cancer human patient derived following treatment with either Dasatinib (30 nM) or Bafetinib (10 μM) inhibitor. As a loading control, total cell lysates were blotted for α-Tubulin.
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Figure 5: Dasatinib treatment increases, while Bafetinib treatment lowers, Claudin-2 levels in breast cancer patient derived xenograft explantsImmunoblot analysis of Claudin-2 expression in GCRC1735 (A) or HCI010 (B) explants derived from triple negative breast cancer human patient derived following treatment with either Dasatinib (30 nM) or Bafetinib (10 μM) inhibitor. As a loading control, total cell lysates were blotted for α-Tubulin.

Mentions: We next examined the potential relevance of our findings to additional human breast cancer models using a breast cancer patient-derived xenograft (PDX) developed in-house (GCRC1735) or a previously described triple negative breast cancer patient-derived xenograft (HCI010) [30]. As observed with human (MDA-MB-231 and BRC31) and mouse (2776) breast cancer cells (Figure 1), we observed an increase in Claudin-2 levels when GCRC1735 PDX cells were treated with Dasatinib (Figure 5A). However, no change in Claudin-2 levels was observed in the HCI010 PDX explant (Figure 5B).


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

Tabariès S, Annis MG, Hsu BE, Tam CE, Savage P, Park M, Siegel PM - Oncotarget (2015)

Dasatinib treatment increases, while Bafetinib treatment lowers, Claudin-2 levels in breast cancer patient derived xenograft explantsImmunoblot analysis of Claudin-2 expression in GCRC1735 (A) or HCI010 (B) explants derived from triple negative breast cancer human patient derived following treatment with either Dasatinib (30 nM) or Bafetinib (10 μM) inhibitor. As a loading control, total cell lysates were blotted for α-Tubulin.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496232&req=5

Figure 5: Dasatinib treatment increases, while Bafetinib treatment lowers, Claudin-2 levels in breast cancer patient derived xenograft explantsImmunoblot analysis of Claudin-2 expression in GCRC1735 (A) or HCI010 (B) explants derived from triple negative breast cancer human patient derived following treatment with either Dasatinib (30 nM) or Bafetinib (10 μM) inhibitor. As a loading control, total cell lysates were blotted for α-Tubulin.
Mentions: We next examined the potential relevance of our findings to additional human breast cancer models using a breast cancer patient-derived xenograft (PDX) developed in-house (GCRC1735) or a previously described triple negative breast cancer patient-derived xenograft (HCI010) [30]. As observed with human (MDA-MB-231 and BRC31) and mouse (2776) breast cancer cells (Figure 1), we observed an increase in Claudin-2 levels when GCRC1735 PDX cells were treated with Dasatinib (Figure 5A). However, no change in Claudin-2 levels was observed in the HCI010 PDX explant (Figure 5B).

Bottom Line: 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.The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis.

View Article: PubMed Central - PubMed

Affiliation: Goodman 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.

No MeSH data available.


Related in: MedlinePlus