Inhibition of the p38 kinase suppresses the proliferation of human ER-negative breast cancer cells.
Cancer Res
; 69(23): 8853-61, 2009 Dec 01.
Article
in En
| MEDLINE
| ID: mdl-19920204
ABSTRACT
p38 kinases are members of the mitogen-activated protein kinase family that transduce signals from various environmental stresses, growth factors, and steroid hormones. p38 is highly expressed in aggressive and invasive breast cancers. Increased levels of activated p38 are markers of poor prognosis. In this study, we tested the hypothesis that blockade of p38 signaling would inhibit breast cancer cell proliferation. We studied breast cancer cell proliferation and cell cycle regulation upon p38 blockade by using three independent approaches dominant-negative (DN) constructs, small interfering RNA (siRNA), and small molecule inhibitors. p38alpha and p38delta are the most abundant isoforms expressed by all examined human breast tumors and breast cancer cell lines. Expression of a DN p38 inhibited both anchorage-dependent and -independent proliferation of MDA-MB-468 cells. Silencing of p38alpha, but not p38delta, using siRNA suppressed MDA-MB-468 cell proliferation. Pharmacologic inhibitors of p38 significantly inhibited the proliferation of p53 mutant and ER-negative breast cancer cells. Whereas p38 has previously been considered as a mediator of stress-induced apoptosis, we propose that p38 may have dual activities regulating survival and proliferation depending on the expression of p53. Our data suggest that p38 mediates the proliferation signal in breast cancer cells expressing mutant but not wild-type p53. Because most ER-negative breast tumors express mutant p53, our results provide the foundation for future development of p38 inhibitors to target p38 for the treatment of p53 mutant and ER-negative breast cancers.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Breast Neoplasms
/
P38 Mitogen-Activated Protein Kinases
Type of study:
Prognostic_studies
Limits:
Female
/
Humans
Language:
En
Journal:
Cancer Res
Year:
2009
Type:
Article
Affiliation country:
United States