Lung tumorigenesis associated with erb-B-2 and erb-B-3 overexpression in human erb-B-3 transgenic mice is enhanced by methylnitrosourea.
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.
Zhou
Hang
H
Division of Hematology/Oncology and Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio, OH 44106-4937, USA.
Liu
Lili
L
Lee
Keunmyoung
K
Qin
Xiusheng
X
Grasso
Adam W
AW
Kung
Hsing-Jien
HJ
Willis
Joesph E
JE
Kern
Jeffery
J
Wagner
Thomas
T
Gerson
Stanton L
SL
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
D008770:Methylnitrosourea