Kindlin-1 promotes pulmonary breast cancer metastasis

Sana Sarvi, Hitesh Patel, Jun Li, Georgia L. Dodd, Helen Creedon, Morwenna Muir, Jocelyn Ward, John C. Dawson, Martin Lee, Jayne Culley, Donald M. Salter, Andrew H. Sims, Adam Byron, Valerie G. Brunton

Research output: Contribution to journalArticlepeer-review

Abstract

In breast cancer, increased expression of the cytoskeletal adaptor protein Kindlin-1 has been linked to increased risks of lung metastasis, but the functional basis is unknown. Here we show that in a mouse model of polyomavirus middle T antigeninduced mammary tumorigenesis, loss of Kindlin-1 reduced early pulmonary arrest and later development of lung metastasis. This phenotype relied on the ability of Kindlin-1 to bind and activate B integrin heterodimers. Kindlin-1 loss reduced c4 integrin-mediated adhesion of mammary tumor cells to the adhesion molecule VCAM-1 on endothelial cells. Treating mice with an anti-VCAM-1 blocking antibodyprevented early pulmonary arrest. Kindlin-1 loss also resulted in reduced secretion of several factors linked to metastatic spread, including the lung metastasis regulator tenascin-C, showing that Kindlin-1 regulated metastatic dissemination by an additional mechanism in the tumor microenvironment. Overall, our results show that Kindlin-1 contributes functionally to early pulmonary metastasis of breast cancer.
Original languageEnglish
Pages (from-to)1484-1496
Number of pages13
JournalCancer Research
Volume78
Issue number6
Early online date12 Jan 2018
DOIs
Publication statusE-pub ahead of print - 12 Jan 2018

Keywords

  • Kindlin-1
  • adhesion
  • METASTASIS

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