title: 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.
authors.affiliation: Department of Pathology, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands.
authors.forename: Marije M
authors.initials: MM
authors.lastname: Vleugel
authors.forename: Astrid E
authors.initials: AE
authors.lastname: Greijer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Bos
authors.forename: Elsken
authors.initials: E
authors.lastname: van der Wall
authors.forename: Paul J
authors.initials: PJ
authors.lastname: van Diest
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000098:blood supply / Q000145:classification / Q000201:enzymology* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D049109:Cell Proliferation; D004789:Enzyme Activation; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology; D016755:Proto-Oncogene Proteins c-jun / Q000032:analysis*; D016019:Survival Analysis; D013629:Tamoxifen / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D016755:Proto-Oncogene Proteins c-jun; D013629:Tamoxifen