p21(WAF1/CIP1) mediates the growth response to TGF-beta in human epithelial cells.
We investigated the mechanism by which cancers evade the growth inhibitory effects of TGF-beta. Using two p21-/- somatically deleted human epithelial cell lines, we find that TGF-beta serves as a growth stimulator rather than a growth suppressor to cells lacking p21. In addition, TGF-beta stimulated p21-/- cells exhibited a mesenchymal phenotype, demonstrated by an upregulation of vimentin and decreased expression of E-cadherin. Analysis of primary human breast cancers by immunohistochemical labeling confirmed a correlation between p21 loss and positive vimentin expression. These data provide a molecular mechanism explaining how nongastrointestinal cancers can escape the anti-proliferative effects of this cytokine and simultaneously use this pathway for growth advantage.
Bachman
Kurtis E
KE
The Sidney Kimmel Comprehensive Canter Center at Johns Hopkins, The Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, Maryland 21231, USA.
Blair
Brian G
BG
Brenner
Keith
K
Bardelli
Alberto
A
Arena
Sabrina
S
Zhou
Shibin
S
Hicks
Jessica
J
De Marzo
Angelo M
AM
Argani
Pedram
P
Park
Ben Ho
BH
D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D015820:Cadherins / Q000378:metabolism; D002455:Cell Division; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014746:Vimentin / Q000378:metabolism
C493956:CDKN1A protein, human; D015820:Cadherins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D016212:Transforming Growth Factor beta; D014746:Vimentin