c-Jun activation is associated with proliferation and angiogenesis in invasive breast cancer

Abstract

c-Jun is a component of the transcription factor activator protein 1 (AP-1), which binds and activates transcription at TRE/AP-1 elements. Extra- or intracellular signals, including growth factors, transforming oncoproteins, and UV irradiation, stimulate phosphorylation of c-Jun at serine 63/73 and activate c-Jun–dependent transcription. Therefore, activated c-Jun potentially plays an important role in carcinogenesis and cancer progression. To evaluate expression patterns of activated c-Jun in breast cancer in relation to angiogenesis and proliferation, we performed immunohistochemistry on 103 cases of invasive breast cancer with an antibody recognizing phosphorylated c-Jun at serine 73. Activated c-Jun showed a predominantly nuclear expression at the invasive front in 38% of invasive breast cancer cases. Furthermore, expression of activated c-Jun was seen in mitotic cells of the invasive front in 50% of cases. Occasionally, fibroblasts, endothelial cells, and benign breast cells showed nuclear expression. Activated nuclear c-Jun expression showed positive correlations with expression of hyperphosphorylated pRb, vascular endothelial growth factor, and with microvessel density. Mitotic c-Jun expression was associated with pRb and microvessel density. Stromal c-Jun expression showed positive relations with microvessel density. In survival analysis, no significant relation was found with activated c-Jun expression and survival, although a trend with poor survival was found for mitotic cells overexpressing activated c-Jun ( P = .09). Our results show that activated c-Jun is predominantly expressed at the invasive front in breast cancer and is associated with proliferation and angiogenesis. Earlier studies have established a functional, in vitro link between activated c-Jun and tumor angiogenesis. Our present results in breast cancer patients confirm this relation in vivo for the first time. Therefore, c-Jun/AP-1 targeting may provide new ways to block tumor angiogenesis.