Afadin cooperates with claudin-2 to promote breast cancer metastasis

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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)180-193
Number of pages14
JournalGenes and Development
Volume33
Issue number3-4
DOIs
StatePublished - Feb 2019

Keywords

  • Afadin
  • Breast cancer
  • Claudin-2
  • Liver metastasis
  • Lung metastasis

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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