Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 15855-15860 |
| Number of pages | 6 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Volume | 106 |
| Issue number | 37 |
| DOIs | |
| State | Published - Sep 15 2009 |
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Keywords
- Breast cancer
- Knockout mice
- Mouse models
- Protein kinase
ASJC Scopus subject areas
- General
Cite this
The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis. / Wertheim, Gerald B W; Yang, Thomas W.; Pan, Tien Chi; Ramne, Anna; Liu, Zhandong; Gardner, Heather P.; Dugan, Katherine D.; Kristel, Petra; Kreike, Bas; Van De Vijver, Marc J.; Cardiff, Robert; Reynolds, Carol; Chodosh, Lewis A.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 37, 15.09.2009, p. 15855-15860.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The Snf1-related kinase, Hunk, is essential for mammary tumor metastasis
AU - Wertheim, Gerald B W
AU - Yang, Thomas W.
AU - Pan, Tien Chi
AU - Ramne, Anna
AU - Liu, Zhandong
AU - Gardner, Heather P.
AU - Dugan, Katherine D.
AU - Kristel, Petra
AU - Kreike, Bas
AU - Van De Vijver, Marc J.
AU - Cardiff, Robert
AU - Reynolds, Carol
AU - Chodosh, Lewis A.
PY - 2009/9/15
Y1 - 2009/9/15
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Knockout mice
KW - Mouse models
KW - Protein kinase
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UR - http://www.scopus.com/inward/citedby.url?scp=70349445613&partnerID=8YFLogxK
U2 - 10.1073/pnas.0906993106
DO - 10.1073/pnas.0906993106
M3 - Article
VL - 106
SP - 15855
EP - 15860
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 37
ER -