14-3-3σ stabilizes a complex of soluble actin and intermediate filament to enable breast tumor invasion.
The protein 14-3-3σ (stratifin) is frequently described as a tumor suppressor silenced in about 80% of breast tumors. Intriguingly, we show that 14-3-3σ expression, which in normal breast is localized to the myoepithelial cells, tracks with malignant phenotype in two models of basal-like breast cancer progression, and in patients, it is associated with basal-like subtype and poor clinical outcome. We characterized a mechanism by which 14-3-3σ guides breast tumor invasion by integrating cytoskeletal dynamics: it stabilizes a complex of solubilized actin and intermediate filaments to maintain a pool of "bioavailable" complexes for polarized assembly during migration. We show that formation of the actin/cytokeratin/14-3-3σ complex and cellular migration are regulated by PKCζ-dependent phosphorylation, a finding that could form the basis for intervention in aggressive breast carcinomas expressing 14-3-3σ. Our data suggest that the biology of this protein is important in cellular movement and is contingent on breast cancer subtype.
Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720.
Aaron
A
Boudreau
Kandice
K
Tanner
Daojing
D
Wang
Felipe C
FC
Geyer
Jorge S
JS
Reis-Filho
Mina J
MJ
Bissell
D048948:14-3-3 Proteins / Q000378:metabolism*; D000199:Actins / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D002460:Cell Line; D005260:Female; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007382:Intermediate Filaments / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D046228:Microarray Analysis; D018613:Microscopy, Confocal; D009361:Neoplasm Invasiveness / Q000503:physiopathology*
D048948:14-3-3 Proteins; D000199:Actins; C499130:Sfn protein, mouse
14-3-3 family; basal breast cancer; cytoskeleton; motility; triple-negative