The mitogen-activated protein kinases (MAPK) p38 and JNK are markers of tumor progression in breast carcinoma

Abstract

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.