Biological and clinical associations of c-jun activation in human breast cancer

Sub-units and regulators of the activating protein-1(AP-1) complex have been implicated in breast-cancer biology, therapeutic response and prognosis. This study has immunocytochemically examined the impact of c-jun-protein activation on biological and clinical parameters in human primary breast cancers, employing an antibody specific for the serine 63-phosphorylated c-jun protein. Substantial nuclear immunostaining was commonly apparent, indicative of an activated c-jun pool, with associations with MAP-kinase-signalling elements, e.g., transforming growth factor-alpha (p = 0.04), epidermal growth factor receptor (p = 0.08), phosphorylated erk 1/2 MAP kinase (p = 0.001) and phosphorylated jun kinase (p = 0.05) Little association was noted with c-fos protein, perhaps indicating alternative AP-1 partners for c-jun with a diversity of cellular end-points. This may explain the lack of relationship with proliferation and grade, the imperfect association between increased c-jun activation and poorer survival (p = 0.061), and the apparent relationship with distant metastasis (p = 0.05). While increased c-jun activation related to poorer quality (p = 0.09) and shortened duration of endocrine response in oestrogen-receptor-positive patients (p = 0.018), no generalized effects on oestrogen-regulated gene products were noted, indicating that AP-1 influences on oestrogen-receptor/oestrogen-response element transactivation are unlikely to explain endocrine insensitivity. These data reinforce our belief that elevated AP-1 signalling influences aspects of the breast-cancer phenotype.