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Genes Dev. 2019 Feb 1;33(3-4):180-193. doi: 10.1101/gad.319194.118. Epub 2019 Jan 28.

Afadin cooperates with Claudin-2 to promote breast cancer metastasis.

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Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.
Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada.
Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.
Department of Pathology, McGill University Health Centre, Montréal, Québec H4A 3J1, Canada.
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614, USA.
Stanley Manne Children's Research Institute, Chicago, Illinois 60614, USA.
Department of Human Genetics, McGill University, Montréal, Québec H3A 1A3, Canada.
Division of Oncology, Department of Clinical Sciences, Lund University, Lund SE 221 00, Sweden.


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.


Afadin; Claudin-2; breast cancer; liver metastasis; lung metastasis

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