The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis.
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.
Wertheim
Gerald B W
GB
Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6160, USA.
Yang
Thomas W
TW
Pan
Tien-chi
TC
Ramne
Anna
A
Liu
Zhandong
Z
Gardner
Heather P
HP
Dugan
Katherine D
KD
Kristel
Petra
P
Kreike
Bas
B
van de Vijver
Marc J
MJ
Cardiff
Robert D
RD
Reynolds
Carol
C
Chodosh
Lewis A
LA
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary*; D002465:Cell Movement / Q000235:genetics / Q000502:physiology; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology* / Q000235:genetics / Q000556:secondary*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000503:physiopathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000503:physiopathology; D011379:Prognosis; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D011494:Protein Kinases; C071570:SNF1-related protein kinases; C417729:Hunk protein, mouse; D017346:Protein Serine-Threonine Kinases