title: Lung tumorigenesis associated with erb-B-2 and erb-B-3 overexpression in human erb-B-3 transgenic mice is enhanced by methylnitrosourea.
abstract: Erb-B-3 overexpression is associated with poor prognosis in non-small cell lung cancer and is often overexpressed in breast cancers. MMTVhuman-erb-B-3 transgenic mice were generated to evaluate the impact of erb-B-3 overexpression on lung and mammary gland tumorigenesis. These transgenic mice developed a high incidence of lung adenocarcinomas but not mammary gland tumors. The tumors overexpressed transgenic human [h]-erb-B-3 but also overexpressed endogenous erb-B-2, indicating that the heterodimer of h-erb-B-3-erb-B-2 was required for proliferative signal transduction to the nucleus. Lung tumor latency was shorter and the incidence higher in erb-B-3 transgenic mice treated with the methylating agent, methylnitrosourea [MNU]. In MNU treated mice, K-ras activating point mutations in codon 12, synergized with h-erb-B-3 in lung tumorogenesis. In bitransgenic MMTVrat-erb-B2/MMTV-human-erb-B-3 mice, lung tumor latency was also significantly shortened. Unlike over-expression of rat-erb-B-2, overexpression of h-erb-B-3 did not alter the incidence or latency of mammary tumors. Coupled erb-B-2 and erb-B-3 overexpression as well as K-ras activation induced signaling through mitogen-activated protein kinase (MAPK). This animal model links erb-B-3 with lung cancer, suggests that erb-B-2 and erb-B-3 heterodimerization is a necessary intermediate, and documents latency shortening by methylating agent-induced mutation of K-ras. This erb-B-3 mouse lung cancer model will help dissect genetic changes in lung tumorigenesis and may be useful for chemoprevention studies.
authors.affiliation: Division of Hematology/Oncology and Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, OH 44106-4937, USA.
authors.forename: Hang
authors.initials: H
authors.lastname: Zhou
authors.forename: Lili
authors.initials: L
authors.lastname: Liu
authors.forename: Keunmyoung
authors.initials: K
authors.lastname: Lee
authors.forename: Xiusheng
authors.initials: X
authors.lastname: Qin
authors.forename: Adam W
authors.initials: AW
authors.lastname: Grasso
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.forename: Joesph E
authors.initials: JE
authors.lastname: Willis
authors.forename: Jeffery
authors.initials: J
authors.lastname: Kern
authors.forename: Thomas
authors.initials: T
authors.lastname: Wagner
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
mesh_terms: D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000139:chemically induced / Q000235:genetics*; D018815:Genes, erbB; D018734:Genes, erbB-2; D011905:Genes, ras; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics*; D008770:Methylnitrosourea / Q000633:toxicity*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019076:Transgenes
chemical_list: D008770:Methylnitrosourea