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

Oncotarget. 2015 Apr 20;6(11):9476-87. doi: 10.18632/oncotarget.3269.

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.

Keywords: Lyn; Src family kinase; breast cancer; claudins; liver metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma / genetics
  • Carcinoma / prevention & control
  • Carcinoma / secondary*
  • Cell Line, Tumor
  • Claudins / biosynthesis*
  • Claudins / genetics
  • Dasatinib / pharmacology
  • Dasatinib / therapeutic use
  • Female
  • Gene Expression Regulation, Neoplastic* / drug effects
  • Humans
  • Liver Neoplasms / prevention & control
  • Liver Neoplasms / secondary*
  • Mammary Neoplasms, Experimental / genetics
  • Mammary Neoplasms, Experimental / pathology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Targeted Therapy*
  • Neoplasm Proteins / antagonists & inhibitors
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Proto-Oncogene Proteins c-fos / physiology
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • RNA Interference
  • RNA, Messenger / biosynthesis
  • RNA, Messenger / genetics
  • RNA, Neoplasm / biosynthesis
  • RNA, Neoplasm / genetics
  • Signal Transduction
  • Transcription Factor AP-1 / physiology
  • Transcription, Genetic
  • Triple Negative Breast Neoplasms / genetics
  • Triple Negative Breast Neoplasms / pathology*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / physiology*

Substances

  • AG 1879
  • CLDN2 protein, human
  • Claudins
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-fos
  • Pyrimidines
  • RNA, Messenger
  • RNA, Neoplasm
  • Transcription Factor AP-1
  • lyn protein-tyrosine kinase
  • src-Family Kinases
  • bafetinib
  • Dasatinib