title: HER-2/neu mediates oncogenic transformation via altered CREB expression and function.
abstract: The cyclic (c)AMP responsive element binding protein (CREB) plays a key role in many cellular processes, including differentiation, proliferation, and signal transduction. Furthermore, CREB overexpression was found in tumors of distinct origin and evidence suggests an association with tumorigenicity. To establish a mechanistic link between HER-2/neu-mediated transformation and CREB protein expression and function, in vitro models of HER-2/neu-overexpressing and HER-2/neu-negative/silenced counterparts as well as human mammary carcinoma lesions with defined HER-2/neu status were used. HER-2/neu overexpression resulted in the induction and activation of CREB protein in vitro and in vivo, whereas short hairpin RNA (shRNA)-mediated inhibition of HER-2/neu correlated with downregulated CREB activity. CREB activation in HER-2/neu-transformed cells enhanced distinct signal transduction pathways, whereas their inhibition negatively interfered with CREB expression and/or activation. CREB downregulation in HER-2/neu-transformed cells by shRNA and by the inhibitors KG-501 and lapatinib caused morphologic changes, reduced cell proliferation with G0-G1 cell-cycle arrest, which was rescued by CREB expression. This was accompanied by reduced cell migration, wound healing, an increased fibronectin adherence, invasion, and matrix metalloproteinase expression. In vivo shCREB-HER-2/neu(+) cells, but not control cells, exerted a significantly decreased tumorgenicity that was associated with decreased proliferative capacity, enhanced apoptosis, and increased frequency of T lymphocytes in peripheral blood mononuclear cells. Thus, CREB plays an important role in the HER-2/neu-mediated transformation by altering in vitro and in vivo growth characteristics.
  
  
  CONCLUSIONS
  These data suggest that CREB affects tumor immunogenicity and is a potential target for cancer therapy.
authors.affiliation: Institute of Medical Immunology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112 Halle, Germany. Barbara.Seliger@uk-halle.de.
authors.forename: André
authors.initials: A
authors.lastname: Steven
authors.forename: Sandra
authors.initials: S
authors.lastname: Leisz
authors.forename: Chiara
authors.initials: C
authors.lastname: Massa
authors.forename: Manuela
authors.initials: M
authors.lastname: Iezzi
authors.forename: Rossano
authors.initials: R
authors.lastname: Lattanzio
authors.forename: Alessia
authors.initials: A
authors.lastname: Lamolinara
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bukur
authors.forename: Anja
authors.initials: A
authors.lastname: Müller
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hiebl
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Holzhausen
authors.forename: Barbara
authors.initials: B
authors.lastname: Seliger
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D017362:Cyclic AMP Response Element-Binding Protein / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D041681:NIH 3T3 Cells; D010641:Phenotype; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D046888:Tissue Array Analysis
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D018719:Erb-b2 Receptor Tyrosine Kinases