title: Carcinoma initiation via RB tumor suppressor inactivation: a versatile approach to epithelial subtype-dependent cancer initiation in diverse tissues.
abstract: Carcinomas arise in a complex microenvironment consisting of multiple distinct epithelial lineages surrounded by a variety of stromal cell types. Understanding cancer etiologies requires evaluating the relationship among cell types during disease initiation and through progression. Genetically engineered mouse (GEM) models facilitate the prospective examination of early oncogenic events, which is not possible in humans. Since most solid tumors harbor aberrations in the RB network, we developed an inducible GEM approach for the establishment and assessment of carcinoma initiation in a diverse range of epithelial tissues and subtypes upon inactivation of RB-mediated tumor suppression (RB-TS). The system allows independent assessment of epithelial subtypes that express either cytokeratins (K) 18 or 19. By Cre-dependent expression of a protein that dominantly inactivates RB and functionally redundant proteins p107 and p130, neoplasia could be initiated in either K18 or K19 expressing cells of numerous tissues. By design, because only a single pathway aberration was engineered, carcinomas developed stochastically only after long latency. Hence, this system, which allows for directed cell type-specific carcinoma initiation, facilitates further definition of events that can progress neoplasms to aggressive cancers via engineered, carcinogen-induced and/or spontaneous evolution.
authors: Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, Maryland, United States of America.
authors: Yurong
authors: Y
authors: Song
authors: Debra
authors: D
authors: Gilbert
authors: T Norene
authors: TN
authors: O'Sullivan
authors: Chunyu
authors: C
authors: Yang
authors: Wenqi
authors: W
authors: Pan
authors: Alisan
authors: A
authors: Fathalizadeh
authors: Lucy
authors: L
authors: Lu
authors: Diana C
authors: DC
authors: Haines
authors: Philip L
authors: PL
authors: Martin
authors: Terry
authors: T
authors: Van Dyke
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D053538:Keratin-18 / Q000096:biosynthesis / Q000235:genetics; D053539:Keratin-19 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D053538:Keratin-18; D053539:Keratin-19; D016160:Retinoblastoma Protein