Afadin cooperates with Claudin-2 to promote breast cancer metastasis

Research output: Contribution to journalArticle

Abstract

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that the PDZ-binding motif of Claudin-2 is necessary for anchorage-independent growth of cancer cells and is required for liver metastasis. Several PDZ domain-containing proteins were identified that interact with the PDZ-binding motif of Claudin-2 in liver metastatic breast cancer cells, including Afadin, Arhgap21, Pdlim2, Pdlim7, Rims2, Scrib, and ZO-1. We specifically examined the role of Afadin as a potential Claudin-2-interacting partner that promotes breast cancer liver metastasis. Afadin associates with Claudin-2, an interaction that requires the PDZ-binding motif of Claudin-2. Loss of Afadin also impairs the ability of breast cancer cells to form colonies in soft agar and metastasize to the lungs or liver. Immunohistochemical analysis of Claudin-2 and/or Afadin expression in 206 metastatic breast cancer tumors revealed that high levels of both Claudin-2 and Afadin in primary tumors were associated with poor disease-specific survival, relapse-free survival, lung-specific relapse, and liver-specific relapse. Our findings indicate that signaling downstream from a Claudin-2/Afadin complex enables the efficient formation of breast cancer metastases. Moreover, combining Claudin-2 and Afadin as prognostic markers better predicts the potential of breast cancer to metastasize to soft tissues.

Details

Authors
  • Sébastien Tabariès
  • Alexander McNulty
  • Véronique Ouellet
  • Matthew G. Annis
  • Mireille Dessureault
  • Maude Vinette
  • Yasmina Hachem
  • Brennan Lavoie
  • Atilla Omeroglu
  • Hans Georg Simon
  • Logan A. Walsh
  • Siker Kimbung
  • Ingrid Hedenfalk
  • Peter M. Siegel
Organisations
External organisations
  • McGill University
  • Centre hospitalier de l'Université de Montréal
  • McGill University Health Center
  • Northwestern University
  • Ann and Robert H. Lurie Children's Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology

Keywords

  • Afadin, breast cancer, Claudin-2, liver metastasis, lung metastasis
Original languageEnglish
Pages (from-to)180-193
Number of pages14
JournalGenes & Development
Volume33
Issue number3-4
StatePublished - 2019
Publication categoryResearch
Peer-reviewedYes