[Correlation of p38 mitogen-activated protein kinase signal transduction pathway to uPA expression in breast cancer].
OBJECTIVE
p38 mitogen-activated protein kinase (p38MAPK) signal transduction pathway regulates the expression of various metastasis-related genes. Urokinase-type plasminogen activator (uPA) plays an important role in cancer invasion and metastasis. This study was to explore the correlation of p38MAPK signal transduction pathway to uPA expression in breast cancer.


METHODS
SP immunohistochemistry was used to test the expression of p-p38, p-Akt, p-Erk, and uPA in 60 specimens of breast cancer. Western blot was used to detect the protein levels of p-p38 and uPA in breast cancer MDA-MB-231 and MCF-7 cells and the protein level of uPA in MDA-MB-231 cells after blocking p38MAPK signal transduction pathway by SB203580, a specific inhibitor of p38MAPK. The correlations of p-p38, p-Akt, p-Erk, and uPA expression to the clinicopathologic characteristics of breast cancer, and the correlations of p-p38, p-Akt, and p-Erk expression to uPA expression were analyzed. The mechanism of p38MAPK signal transduction pathway regulating the protein expression of uPA in breast cancer cells was investigated. The correlation of p-p38 and uPA expression to prognosis of breast cancer was analyzed.


RESULTS
The positive rates of p-p38, p-Akt, p-Erk, and uPA proteins in breast cancer tissues were 56.7%, 95.0%, 93.3%, and 60.0%, respectively. The expression of p-p38 was positively correlated to the expression of uPA (r=0.316, P<0.05), while the expression of p-Akt and p-Erk was not related to uPA expression. The expression of p-p38 and uPA was correlated to lymph node metastasis and TNM stage (P<0.05), but not to patients' age and tumor size (P>0.05). The expression of p-Akt and p-Erk were correlated to lymph node metastasis (P<0.05), but not to TNM stage, patients' age, and tumor size (P>0.05). The protein levels of p-p38 and uPA in MDA-MB-231 cells were higher than that in MCF-7 cells. SB203580 concentration-dependently inhibited p38MAPK pathway and induced uPA protein expression. The expression of p-p38 and uPA was negatively correlated to prognosis of breast cancer (log-rank=4.98, 5.40, P=0.026, 0.020).


CONCLUSIONS
p38MAPK signal transduction pathway might improve breast cancer progression by up-regulating uPA expression, and might be an important route in invasion and metastasis of breast cancer. p-p38 and uPA might help to evaluate prognosis of breast cancer.
Han
Yan-Chun
YC
Department of Pathology, Basic Medical School, China Medical University, Shenyang, Liaoning, 110001, P. R. China.
Zeng
Xian-Xu
XX
Wang
Rui
R
Zhao
Yan
Y
Li
Bai-Lin
BL
Song
Min
M
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008207:Lymphatic Metastasis; D008875:Middle Aged; D009367:Neoplasm Staging; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D014568:Urokinase-Type Plasminogen Activator; C093642:SB 203580