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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.

Author information

1
Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.
2
Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.
3
Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada.
4
Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada.
5
Department of Pathology, McGill University Health Centre, Montréal, Québec H4A 3J1, Canada.
6
Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614, USA.
7
Stanley Manne Children's Research Institute, Chicago, Illinois 60614, USA.
8
Department of Human Genetics, McGill University, Montréal, Québec H3A 1A3, Canada.
9
Division of Oncology, Department of Clinical Sciences, Lund University, Lund SE 221 00, Sweden.

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.

KEYWORDS:

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

PMID:
30692208
PMCID:
PMC6362814
DOI:
10.1101/gad.319194.118
[Indexed for MEDLINE]
Free PMC Article

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