Afadin cooperates with Claudin-2 to promote breast cancer metastasis
- Sébastien Tabariès1,2,
- Alexander McNulty1,3,
- Véronique Ouellet4,
- Matthew G. Annis1,2,
- Mireille Dessureault1,2,
- Maude Vinette1,2,
- Yasmina Hachem1,3,
- Brennan Lavoie1,2,
- Atilla Omeroglu5,
- Hans-Georg Simon6,7,
- Logan A. Walsh1,8,
- Siker Kimbung9,
- Ingrid Hedenfalk9 and
- Peter M. Siegel1,2,3
- 1Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada;
- 2Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada;
- 3Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada;
- 4Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada;
- 5Department of Pathology, McGill University Health Centre, Montréal, Québec H4A 3J1, Canada;
- 6Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614, USA;
- 7Stanley Manne Children's Research Institute, Chicago, Illinois 60614, USA;
- 8Department of Human Genetics, McGill University, Montréal, Québec H3A 1A3, Canada;
- 9Division of Oncology, Department of Clinical Sciences, Lund University, Lund SE 221 00, Sweden
- Corresponding author: peter.siegel{at}mcgill.ca
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.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.319194.118.
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Freely available online through the Genes & Development Open Access option.
- Received July 22, 2018.
- Accepted November 19, 2018.
This article, published in Genes & Development, is available under a Creative Commons License (Attribution 4.0 International), as described at http://creativecommons.org/licenses/by/4.0/.