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

• Published in: Human pathology Vol. 37; no. 6; pp. 668 - 674
• Main Authors: Vleugel, Marije M., Greijer, Astrid E., Bos, Reinhard, van der Wall, Elsken, van Diest, Paul J.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.06.2006; Elsevier; Elsevier Limited
• Subjects: Angiogenesis; Antineoplastic Agents, Hormonal - therapeutic use; AP-1; Biological and medical sciences; Breast cancer; Breast Neoplasms - blood supply; Breast Neoplasms - classification; Breast Neoplasms - enzymology; Breast Neoplasms - metabolism; Breast Neoplasms - mortality; Breast Neoplasms - pathology; c-Jun; Cell Proliferation; Enzyme Activation; Female; Follow-Up Studies; Gynecology. Andrology. Obstetrics; Humans; Immunohistochemistry; Investigative techniques, diagnostic techniques (general aspects); Kinases; Mammary gland diseases; Medical sciences; Neoplasm Invasiveness; Neoplasm Recurrence, Local; Neovascularization, Pathologic - metabolism; Neovascularization, Pathologic - pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Proliferation; Proteins; Proto-Oncogene Proteins c-jun - analysis; Rodents; Survival Analysis; Tamoxifen - therapeutic use; Time Factors; Treatment Outcome; Tumors; Immunohistochemistry; c-Jun; Angiogenesis; Breast cancer; Proliferation; AP-1; Cell proliferation; Activation; Malignant tumor; Infiltrating tumor; Mammary gland diseases; Anatomic pathology; Association; C-Onc gene; Neovascularization; Transcription factor AP1
• ISSN: 0046-8177; 1532-8392
• DOI: 10.1016/j.humpath.2006.01.022

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.