TY - JOUR
T1 - HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1
AU - Quintela-Fandino, Miguel
AU - Arpaia, Enrico
AU - Brenner, Dirk
AU - Goh, Theo
AU - Yeung, Faith Au
AU - Blaser, Heiko
AU - Alexandrova, Roumiana
AU - Lind, Evan F.
AU - Tusche, Mike W.
AU - Wakeham, Andrew
AU - Ohashi, Pamela S.
AU - Mak, Tak W.
PY - 2010/2/9
Y1 - 2010/2/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77249126947&partnerID=8YFLogxK
U2 - 10.1073/pnas.0914492107
DO - 10.1073/pnas.0914492107
M3 - Article
C2 - 20133759
AN - SCOPUS:77249126947
SN - 0027-8424
VL - 107
SP - 2622
EP - 2627
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
IS - 6
ER -