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The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis

2009; National Academy of Sciences; Volume: 106; Issue: 37 Linguagem: Inglês

10.1073/pnas.0906993106

1091-6490

Gerald Wertheim, Thomas Yang, Tien-Chi Pan, Anna Ramne, Zhandong Liu, Heather Perry Gardner, Katherine D. Dugan, Petra Kristel, Bas Kreike, Marc J. van de Vijver, Robert D. Cardiff, Carol Reynolds, Lewis A. Chodosh,

Metabolism, Diabetes, and Cancer

We previously identified a SNF1/AMPK-related protein kinase, Hunk, from a mammary tumor arising in an MMTV-neu transgenic mouse. The function of this kinase is unknown. Using targeted deletion in mice, we now demonstrate that Hunk is required for the metastasis of c-myc-induced mammary tumors, but is dispensable for normal development. Reconstitution experiments revealed that Hunk is sufficient to restore the metastatic potential of Hunk-deficient tumor cells, as well as defects in migration and invasion, and does so in a manner that requires its kinase activity. Consistent with a role for this kinase in the progression of human cancers, the human homologue of Hunk is overexpressed in aggressive subsets of carcinomas of the ovary, colon, and breast. In addition, a murine gene expression signature that distinguishes Hunk-wild type from Hunk-deficient mammary tumors predicts clinical outcome in women with breast cancer in a manner consistent with the pro-metastatic function of Hunk in mice. These findings identify a direct role for Hunk kinase activity in metastasis and establish an in vivo function for this kinase.