The mitogen-activated protein kinases (MAPK) p38 and JNK are markers of tumor progression in breast carcinoma.
OBJECTIVE
To investigate the activation of mitogen-activated protein kinases (MAPK) in breast carcinoma effusions and to analyze its relationship to anatomic site and clinical parameters.


METHODS
Activated MAPK (p-ERK, p-JNK, and p-p38) expression was studied in 42 effusions and 51 corresponding solid tumors (23 primary, 28 metastases) using immunohistochemistry (IHC). Hormone receptor and HER2 status, proliferation (Ki-67), and apoptosis (p85-PARP fragment) were assessed. MAPK levels, activity, and activation ratio (phospho/pan-MAPK ratio) were analyzed in 19 effusions using immunoblotting (IB).


RESULTS
Nuclear expression of p-p38 and p-JNK was significantly higher in effusions compared with both primary tumors (P < 0.001 for p-JNK, P = 0.011 for p-p38) and lymph node metastases (P = 0.003 for p-JNK, P = 0.025 for p-p38) but was not accompanied by apoptosis. IB showed pan-ERK and p-ERK in 18/19 effusions, pan-JNK and p-JNK in 18/19 and 17/19 effusions, respectively, and pan-p38 and p-p38 in 19/19 and 17/19 specimens, respectively. In univariate survival analysis of all cases, advanced disease stage (P = 0.041), previous chemotherapy (P = 0.004), and radiation (P = 0.001) and higher Ki-67 scores (P = 0.01) correlated with worse overall survival (OS). In Cox multivariate analysis, stage (P = 0.018), chemotherapy (P = 0.024), radiation (P = 0.017), and ER status (P = 0.002) were independent prognosticators of OS. Quantitative analysis of IB data showed that higher p38 activation ratio correlates with shorter OS (P = 0.01).


CONCLUSIONS
This study presents first evidence of in vivo activation of MAPK in breast carcinoma effusions. The elevated JNK and p38 activation in effusions may be a stress-related mechanism providing breast carcinoma cells with survival advantages rather than a drive towards apoptosis. p38 and Ki-67 may be new prognostic markers for patients with breast cancer effusions.
Davidson
Ben
B
Department of Pathology, The National Hospital-Norwegian Radium Hospital, University of Oslo, Montebello N-0310 Oslo, Norway. ben.davidson@radiumhospitalet.no
Konstantinovsky
Sophya
S
Kleinberg
Lilach
L
Nguyen
Mai T P
MT
Bassarova
Assia
A
Kvalheim
Gunnar
G
Nesland
Jahn M
JM
Reich
Reuven
R
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000201:enzymology* / Q000473:pathology; D002277:Carcinoma / Q000201:enzymology* / Q000473:pathology; D002467:Cell Nucleus / Q000201:enzymology; D015331:Cohort Studies; D018450:Disease Progression; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D008875:Middle Aged; D010996:Pleural Effusion / Q000201:enzymology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D015415:Biomarkers; D048031:JNK Mitogen-Activated Protein Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases