HUNK suppresses metastasis of basal type breast cancers by disrupting the interaction between PP2A and cofilin-1.
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 Up-regulated 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.
Campbell Family Institute for Breast Cancer Research, Ontario Cancer Institute at Princess Margaret Hospital, University Health Network, Toronto, ON M5G 2C1, Canada.
Miguel
M
Quintela-Fandino
Enrico
E
Arpaia
Dirk
D
Brenner
Theo
T
Goh
Faith Au
FA
Yeung
Heiko
H
Blaser
Roumiana
R
Alexandrova
Evan F
EF
Lind
Mike W
MW
Tusche
Andrew
A
Wakeham
Pamela S
PS
Ohashi
Tak W
TW
Mak
D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D051338:Cofilin 1 / Q000235:genetics / Q000378:metabolism*; D003599:Cytoskeleton / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011485:Protein Binding; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D014183:Transplantation, Heterologous
D000199:Actins; D051338:Cofilin 1; D011494:Protein Kinases; C549065:HUNK protein, human; C417729:Hunk protein, mouse; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2