title: HER-2 signaling, acquisition of growth factor independence, and regulation of biological networks associated with cell transformation.
abstract: Activated oncogenes are the dominant drivers of malignant progression in human cancer, yet little is known about how the transformation from proto-oncogene to activated oncogene drives the expression of transformed phenotypes. An isogenic model of HER-2-mediated transformation of human mammary epithelial cells was used along with HER-2-amplified human breast cancers to investigate how HER-2 activation alters its properties as a signaling molecule and changes the networks of HER-2-regulated genes. Our results show that full oncogenic activation of HER-2 is the result of a transition in which activated HER-2 acquires dominant signaling properties that qualitatively alter the network of genes regulated by the activated oncogene compared with the proto-oncogene. Consequently, gene expression programs related to invasion, cell stress, and stemness become regulated by HER-2 in a manner not observed in nontransformed cells, even when HER-2 is overexpressed. Our results offer novel insights into biological processes that come under the control of HER-2 after it acquires full oncogenic potential.
authors.affiliation: Breast Cancer Biology Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
authors.forename: Aliccia
authors.initials: A
authors.lastname: Bollig-Fischer
authors.forename: Michele
authors.initials: M
authors.lastname: Dziubinski
authors.forename: Alaina
authors.initials: A
authors.lastname: Boyer
authors.forename: Ramsi
authors.initials: R
authors.lastname: Haddad
authors.forename: Craig N
authors.initials: CN
authors.lastname: Giroux
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Ethier
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000473:pathology*; D004815:Epidermal Growth Factor / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
chemical_list: D004815:Epidermal Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C000715470:MAS1 protein, human; C508053:ERBB2 protein, human