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 be en implicated in breast-cancer biology, therapeutic response and prognosis. This study has immunocytochemically examined the impact of c-jun-protein a ctivation on biological and clinical parameters in human primary breast can cers, employing an antibody specific for the serine 63-phosphorylated c-jun protein. Substantial nuclear immunostaining was commonly apparent, indicat ive of an activated c-jun pool, with associations with MAP-kinase-signallin g elements, e.g, transforming growth factor-alpha (p = 0.04), epidermal gro wth factor receptor (p = 0.08), phosphorylated erk 1/2 MAP kinase (p = 0.00 1) and phosphorylated jun kinase (p = 0.05) Little association war noted wi th c-fos protein, perhaps indicating alternative AP-1 partners for c-jun wi th a diversity of cellular end-points. This may explain the lack of relatio nship with proliferation and grade, the imperfect association between incre ased c-jun activation and poorer survival (p = 0.061), and the apparent rel ationship with distant metastasis (p = 0.05). While increased c-jun activat ion related to poorer quality (p = 0.09) and shortened duration of endocrin e response in oestrogen-receptor-positive patients (p = 0.018), no generali zed effects on oestrogen-regulated gene products were noted, indicating tha t AP-1 influences on oestrogen-receptor/oestrogen-response element transact ivation are unlikely to explain endocrine insensitivity. These data reinfor ce our belief that elevated AP-1 signalling influences aspects of the breas t-cancer phenotype. (C) 2000 Wiley-Liss, Inc.