HER-2 signaling, acquisition of growth factor independence, and regulation of biological networks associated with cell transformation.
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.
Bollig-Fischer
Aliccia
A
Breast Cancer Biology Program, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Dziubinski
Michele
M
Boyer
Alaina
A
Haddad
Ramsi
R
Giroux
Craig N
CN
Ethier
Stephen P
SP
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
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