JNK, essential for anticancer therapy-induced apoptosis, promotes breast cancer progression.

Abstract Abstract #5075 The c-Jun N-terminal kinase (JNK) is a critical mediator of stress-induced apoptosis and is required for the cytotoxic effect of anticancer therapies. Interestingly, recent clinical studies showed that high JNK activity is associated with poor prognosis in human breast cancer. The molecular basis of this potential dual function of JNK in breast cancer is poorly understood. Here we report that overexpression of a constitutively active JNK in breast cancer cells increased cell migration and invasion. In agreement with this, fibroblast-specific markers like the intermediate filament vimentin and the extracellular matrix protein fibronectin were up-regulated. AP-1 transcription factor, which induces expression of these two proteins, was markedly increased by JNK overexpression. In addition, hyperactive JNK reduced Akt1 activation but enhanced Erk activation in breast cancer cells. In relevance, we also found that JNK levels are significantly higher in invasive breast cancers including those with distant metastases (n = 235, p < 0.0001, Wilcoxon rank sum test) than in normal breast tissues (n = 69). Most surprisingly, an increase of JNK attenuated the apoptosis of breast cancer cells treated with chemotherapy drugs doxorubicin and taxol. This suggests that the role of JNK changes when its activity/expression increases above the basal levels associated with apoptosis. Our data, together with a recent finding that cells undergoing cytotoxic agent-induced apoptosis can induce compensatory hyper-proliferation of proximal cancer cells, suggest a novel mechanism of breast cancer therapeutic resistance. Therapy-elicited apoptosis of tumor cells with basal JNK activity may release mitogens that induce hyperactive JNK in neighboring cells to promote growth and invasion. Thus JNK activation may serve as a marker of breast cancer progression. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 5075.