title: Premature senescence is a primary fail-safe mechanism of ERBB2-driven tumorigenesis in breast carcinoma cells.
abstract: The receptor tyrosine kinase ERBB2 plays a central role in the development of breast cancer and other epithelial malignancies. Elevated ERBB2 activity is believed to transform cells by transmitting mitogenic and antiapoptotic signals. Here we show that tightly regulated overexpression of oncogenic ERBB2 in human breast carcinoma cells does not stimulate proliferation but provokes premature senescence, accompanied by up-regulation of the cyclin-dependent kinase inhibitor P21(WAF1/CIP1). A similar effect was caused by retrovirus-mediated overexpression of oncogenic ERBB2 in low-passage murine embryonic fibroblasts. In contrast to previous observations based on constitutively overexpressing cell lines, P21 induced by tetracycline-regulated ERBB2 localizes to the nucleus in arrested cells. P21 up-regulation seems to be independent of the P53 tumor suppressor protein, and senescence-associated phenotypic alterations are reversed by specific inhibition of P38 mitogen-activated protein kinases. Functional inactivation of P21 by antisense oligonucleotides is sufficient to prevent cell cycle arrest as well as the senescent phenotype, thereby identifying the P21 protein as the key mediator of hypermitogenic cell cycle arrest and premature senescence in breast carcinoma cells. Our results may thus indicate that premature senescence represents an inherent anticarcinogenic program during ERBB2-driven mammary tumorigenesis. We propose a multistep model for the process of malignant transformation by ERBB2 wherein secondary lesions either target P21 or downstream effectors of senescence to bypass this primary fail-safe mechanism.
authors.affiliation: Children's Hospital, University of Mainz, Obere Zahlbacher Strasse 63, 55131 Mainz, Germany.
authors.forename: Tatjana M
authors.initials: TM
authors.lastname: Trost
authors.forename: Ekkehart U
authors.initials: EU
authors.lastname: Lausch
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Fees
authors.forename: Steffen
authors.initials: S
authors.lastname: Schmitt
authors.forename: Thorsten
authors.initials: T
authors.lastname: Enklaar
authors.forename: Dirk
authors.initials: D
authors.lastname: Reutzel
authors.forename: Lili R
authors.initials: LR
authors.lastname: Brixel
authors.forename: Peter
authors.initials: P
authors.lastname: Schmidtke
authors.forename: Marko
authors.initials: M
authors.lastname: Maringer
authors.forename: Ilka B
authors.initials: IB
authors.lastname: Schiffer
authors.forename: Carolin K
authors.initials: CK
authors.lastname: Heimerdinger
authors.forename: Jan G
authors.initials: JG
authors.lastname: Hengstler
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fritz
authors.forename: Ernst O
authors.initials: EO
authors.lastname: Bockamp
authors.forename: Dirk
authors.initials: D
authors.lastname: Prawitt
authors.forename: Bernhard U
authors.initials: BU
authors.lastname: Zabel
authors.forename: Christian
authors.initials: C
authors.lastname: Spangenberg
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle / Q000502:physiology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016922:Cellular Senescence / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016376:Oligonucleotides, Antisense; D018719:Erb-b2 Receptor Tyrosine Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C493956:CDKN1A protein, human