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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

Bafetinib treatment impairs the formation of breast cancer liver metastasesImmunoblot analysis of Claudin-2 expression in both human breast cancer cells (MDA-MB-231 and BRC31) (A) or 2776 mouse breast cancer cells (B) following treatment with Bafetinib inhibitor. As a loading control, total cell lysates were blotted for α-Tubulin (A, B). (C) Bafetinib treatment decreases the formation of liver metastases derived from 2776 cells following splenic injection (1 × 105 cells). A statistically significant decrease in both the number of hepatic metastatic lesions or the liver metastatic burden is observed when the control cohort (Par Vehicle) is compared to the Bafetinib-treated cohort (Par Baf) (*, P < 0.05). The number of mice analyzed in each cohort is indicated in parentheses. (D) Representative images of H&E stained liver sections exhibiting the liver metastatic burden in each cohort. Scale bar represents 2mm. Veh, Vehicle; Baf, Lyn inhibitor (Bafetinib).
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Figure 6: Bafetinib treatment impairs the formation of breast cancer liver metastasesImmunoblot analysis of Claudin-2 expression in both human breast cancer cells (MDA-MB-231 and BRC31) (A) or 2776 mouse breast cancer cells (B) following treatment with Bafetinib inhibitor. As a loading control, total cell lysates were blotted for α-Tubulin (A, B). (C) Bafetinib treatment decreases the formation of liver metastases derived from 2776 cells following splenic injection (1 × 105 cells). A statistically significant decrease in both the number of hepatic metastatic lesions or the liver metastatic burden is observed when the control cohort (Par Vehicle) is compared to the Bafetinib-treated cohort (Par Baf) (*, P < 0.05). The number of mice analyzed in each cohort is indicated in parentheses. (D) Representative images of H&E stained liver sections exhibiting the liver metastatic burden in each cohort. Scale bar represents 2mm. Veh, Vehicle; Baf, Lyn inhibitor (Bafetinib).

Mentions: We also assessed whether Bafetinib treatment had the same effect on Claudin-2 levels in multiple breast cancer cell models. Uniformly, Bafetinib treatment reduced Claudin-2 levels in human breast cancer cells and liver-metastatic mouse breast cancer cells (Figure 6A and 6B). We next determined whether Bafetinib treatment would act to suppress the formation of breast cancer liver metastasis in vivo. Following intra-splenic injection of 2776 liver-aggressive breast cancer cells, we observed that mice treated with Bafetinib exhibited a 4-fold decrease in number of hepatic lesions and a 2.3-fold decrease in the formation of liver metastases compared to animals receiving the vehicle control (Figure 6C and 6D). We observed a slight decrease in tumor cell proliferation (Ki67) in hepatic metastases derived from 2776 liver-aggressive breast cancer cells that emerged in mice treatment with Bafetinib (Supplementary Figure 5A). In contrast, the degree of apoptosis (Cleaved Caspase-3) was unchanged in liver metastases that grew in the vehicle or Bafetinib-treated cohorts (Supplementary Figure 5B). Interestingly, the levels of Claudin-2 were clearly diminished in liver metastases from mice treated with Bafetinib compared to vehicle-treated controls (Supplementary Figure 5C), which recapitulate our in vitro findings (Figure 6A and 6B). Together, these observations suggest that, in contrast with the use of Dasatinib (Figure 3), breast cancer patients may benefit from treatment with Bafetinib to manage the formation of liver metastases.


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)

Bafetinib treatment impairs the formation of breast cancer liver metastasesImmunoblot analysis of Claudin-2 expression in both human breast cancer cells (MDA-MB-231 and BRC31) (A) or 2776 mouse breast cancer cells (B) following treatment with Bafetinib inhibitor. As a loading control, total cell lysates were blotted for α-Tubulin (A, B). (C) Bafetinib treatment decreases the formation of liver metastases derived from 2776 cells following splenic injection (1 × 105 cells). A statistically significant decrease in both the number of hepatic metastatic lesions or the liver metastatic burden is observed when the control cohort (Par Vehicle) is compared to the Bafetinib-treated cohort (Par Baf) (*, P < 0.05). The number of mice analyzed in each cohort is indicated in parentheses. (D) Representative images of H&E stained liver sections exhibiting the liver metastatic burden in each cohort. Scale bar represents 2mm. Veh, Vehicle; Baf, Lyn inhibitor (Bafetinib).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: Bafetinib treatment impairs the formation of breast cancer liver metastasesImmunoblot analysis of Claudin-2 expression in both human breast cancer cells (MDA-MB-231 and BRC31) (A) or 2776 mouse breast cancer cells (B) following treatment with Bafetinib inhibitor. As a loading control, total cell lysates were blotted for α-Tubulin (A, B). (C) Bafetinib treatment decreases the formation of liver metastases derived from 2776 cells following splenic injection (1 × 105 cells). A statistically significant decrease in both the number of hepatic metastatic lesions or the liver metastatic burden is observed when the control cohort (Par Vehicle) is compared to the Bafetinib-treated cohort (Par Baf) (*, P < 0.05). The number of mice analyzed in each cohort is indicated in parentheses. (D) Representative images of H&E stained liver sections exhibiting the liver metastatic burden in each cohort. Scale bar represents 2mm. Veh, Vehicle; Baf, Lyn inhibitor (Bafetinib).
Mentions: We also assessed whether Bafetinib treatment had the same effect on Claudin-2 levels in multiple breast cancer cell models. Uniformly, Bafetinib treatment reduced Claudin-2 levels in human breast cancer cells and liver-metastatic mouse breast cancer cells (Figure 6A and 6B). We next determined whether Bafetinib treatment would act to suppress the formation of breast cancer liver metastasis in vivo. Following intra-splenic injection of 2776 liver-aggressive breast cancer cells, we observed that mice treated with Bafetinib exhibited a 4-fold decrease in number of hepatic lesions and a 2.3-fold decrease in the formation of liver metastases compared to animals receiving the vehicle control (Figure 6C and 6D). We observed a slight decrease in tumor cell proliferation (Ki67) in hepatic metastases derived from 2776 liver-aggressive breast cancer cells that emerged in mice treatment with Bafetinib (Supplementary Figure 5A). In contrast, the degree of apoptosis (Cleaved Caspase-3) was unchanged in liver metastases that grew in the vehicle or Bafetinib-treated cohorts (Supplementary Figure 5B). Interestingly, the levels of Claudin-2 were clearly diminished in liver metastases from mice treated with Bafetinib compared to vehicle-treated controls (Supplementary Figure 5C), which recapitulate our in vitro findings (Figure 6A and 6B). Together, these observations suggest that, in contrast with the use of Dasatinib (Figure 3), breast cancer patients may benefit from treatment with Bafetinib to manage the formation of liver metastases.

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