title: Amyloid-β precursor protein promotes cell proliferation and motility of advanced breast cancer.
abstract: BACKGROUND
  Amyloid-β precursor protein (APP) is a highly conserved single transmembrane protein that has been linked to Alzheimer disease. Recently, the increased expression of APP in multiple types of cancers has been reported where it has significant correlation with the cancer cell proliferation. However, the function of APP in the pathogenesis of breast cancer has not previously been determined. In this study, we studied the pathological role of APP in breast cancer and revealed its potential mechanism.
  
  
  METHODS
  The expression level of APP in multiple breast cancer cell lines was measured by Western blot analysis and the breast cancer tissue microarray was utilized to analyze the expression pattern of APP in human patient specimens. To interrogate the functional role of APP in cell growth and apoptosis, the effect of APP knockdown in MDA-MB-231 cells were analyzed. Specifically, multiple signal transduction pathways and functional alterations linked to cell survival and motility were examined in in vivo animal model as well as in vitro cell culture with the manipulation of APP expression.
  
  
  RESULTS
  We found that the expression of APP is increased in mouse and human breast cancer cell lines, especially in the cell line possessing higher metastatic potential. Moreover, the analysis of human breast cancer tissues revealed a significant correlation between the level of APP and tumor development. Knockdown of APP (APP-kd) in breast cancer cells caused the retardation of cell growth in vitro and in vivo, with both the induction of p27(kip1) and caspase-3-mediated apoptosis. APP-kd cells also had higher sensitivity to treatment of chemotherapeutic agents, TRAIL and 5-FU. Such anti-tumorigenic effects shown in the APP-kd cells partially came from reduced pro-survival AKT activation in response to IGF-1, leading to activation of key signaling regulators for cell growth, survival, and pro-apoptotic events such as GSK3-β and FOXO1. Notably, knock-down of APP in metastatic breast cancer cells limited cell migration and invasion ability upon stimulation of IGF-1.
  
  
  CONCLUSIONS
  The present data strongly suggest that the increase of APP expression is causally linked to tumorigenicity as well as invasion of aggressive breast cancer and, therefore, the targeting of APP may be an effective therapy for breast cancer.
authors.affiliation: Department of Pediatrics, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, 2103 Cornell Road, Cleveland, OH 44106, USA. sxl269@case.edu.
authors.forename: Seunghwan
authors.initials: S
authors.lastname: Lim
authors.forename: Byoung Kwon
authors.initials: BK
authors.lastname: Yoo
authors.forename: Hae-Suk
authors.initials: HS
authors.lastname: Kim
authors.forename: Hannah L
authors.initials: HL
authors.lastname: Gilmore
authors.forename: Yonghun
authors.initials: Y
authors.lastname: Lee
authors.forename: Hyun-pil
authors.initials: HP
authors.lastname: Lee
authors.forename: Seong-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: John
authors.initials: J
authors.lastname: Letterio
authors.forename: Hyoung-gon
authors.initials: HG
authors.lastname: Lee
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D009367:Neoplasm Staging; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016564:Amyloid beta-Protein Precursor; D050760:Cyclin-Dependent Kinase Inhibitor p27; D007334:Insulin-Like Growth Factor I; D051057:Proto-Oncogene Proteins c-akt