title: Tumor suppressor genes promote rhabdomyosarcoma progression in p53 heterozygous, HER-2/neu transgenic mice.
abstract: Human sarcomas arise suddenly, thus preempting the study of preneoplastic and early neoplastic lesions. To explore the natural history of these tumors we studied male mice carrying a heterozygous deletion of p53 and an activated HER-2/neu transgene (BALB-p53Neu mice), that develop urethral rhabdomyosarcomas with nearly full penetrance and early onset (4 months of age). Among genes prominently upregulated in preneoplastic tissue, and more highly expressed in tumors, we found the insulin-like growth factor 2 (Igf2) and tumor suppressors, p19Arf and p21Cip1. In urethral tissues of male mice p53 was less expressed than in female mice, whereas HER-2/neu was more expressed, a combination not found in other skeletal muscles of the same mice that could contribute to the anatomic and sexual specificity of BALB-p53Neu rhabdomyosarcoma. Upregulation of p19Arf and p21Cip1 was additively determined by HER-2/neu activation and by p53 inactivation. Silencing of p19Arf or p21Cip1 in rhabdomyosarcoma cell lines can inhibit cell growth and motility, thus suggesting that these genes can contribute to growth autonomy and malignancy of tumor cells. In vivo injection of gene-silenced cells highlighted selective variations in organ-specific metastatic ability, indicating that overexpression of p19Arf and p21Cip1 controlled both tumor cell-intrinsic properties and microenvironmental interactions. The onset of pelvic rhabdomyosarcoma in BALB-p53Neu male mice is triggered by the coincidental overexpression of HER-2/neu and hypoexpression of the residual p53 allele, that foster p53 loss, Igf2 autocriny and overexpression of p19Arf and p21Cip1, a phenotype that could provide novel potential targets for cancer prevention and therapy.
authors: Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna.
authors: Marianna L
authors: ML
authors: Ianzano
authors: Stefania
authors: S
authors: Croci
authors: Giordano
authors: G
authors: Nicoletti
authors: Arianna
authors: A
authors: Palladini
authors: Lorena
authors: L
authors: Landuzzi
authors: Valentina
authors: V
authors: Grosso
authors: Dario
authors: D
authors: Ranieri
authors: Massimiliano
authors: M
authors: Dall'Ora
authors: Ilaria
authors: I
authors: Santeramo
authors: Milena
authors: M
authors: Urbini
authors: Carla
authors: C
authors: De Giovanni
authors: Pier-Luigi
authors: PL
authors: Lollini
authors: Patrizia
authors: P
authors: Nanni
mesh_terms: D000818:Animals; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019076:Transgenes; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53