HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1

Miguel Quintela-Fandino, Enrico Arpaia, Dirk Brenner, Theo Goh, Faith Au Yeung, Heiko Blaser, Roumiana Alexandrova, Evan F. Lind, Mike W. Tusche, Andrew Wakeham, Pamela S. Ohashi, Tak W. Mak

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29 Scopus citations

Abstract

Metastasis leads to the death of most cancer patients, and basal breast cancer is the most aggressive breast tumor type. Metastasis involves a complex cell migration process dependent on cytoskeletal remodeling such that targeting such remodeling in tumor cells could be clinically beneficial. Here we show that Hormonally Upregulated Neu-associated Kinase (HUNK) is dramatically down-regulated in tumor samples and cell lines derived from basal breast cancers. Reconstitution of HUNK expression in basal breast cancer cell lines blocked actin polymerization and reduced cell motility, resulting in decreased metastases in two in vivo murine cancer models. Mechanistically, HUNK overexpression sustained the constitutive phosphorylation and inactivation of cofilin-1 (CFL-1), thereby blocking the incorporation of new actin monomers into actin filaments. HUNK reconstitution in basal breast cancer cell lines prevented protein phosphatase 2-A (PP2A), a phosphatase putatively acting on CFL-1, from binding to CFL-1. Our investigation of HUNK suggests that the interaction between PP2A and CFL-1 may be a target for antimetastasis therapy, particularly for basal breast cancers.

Original languageEnglish (US)
Pages (from-to)2622-2627
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number6
DOIs
StatePublished - Feb 9 2010
Externally publishedYes

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    Quintela-Fandino, M., Arpaia, E., Brenner, D., Goh, T., Yeung, F. A., Blaser, H., Alexandrova, R., Lind, E. F., Tusche, M. W., Wakeham, A., Ohashi, P. S., & Mak, T. W. (2010). HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1. Proceedings of the National Academy of Sciences of the United States of America, 107(6), 2622-2627. https://doi.org/10.1073/pnas.0914492107