Therapy-induced malignant neoplasms in Nf1 mutant mice.
Therapy-induced cancers are a severe complication of genotoxic therapies. We used heterozygous Nf1 mutant mice as a sensitized genetic background to investigate tumor induction by radiation (RAD) and cyclophosphamide (CY). Mutagen-exposed Nf1(+/-) mice developed secondary cancers that are common in humans, including myeloid malignancies, sarcomas, and breast cancers. RAD cooperated strongly with heterozygous Nf1 inactivation in tumorigenesis. Most of the solid tumors showed loss of the wild-type Nf1 allele but retained two Trp53 alleles. Comparative genomic hybridization demonstrated distinct patterns of copy number aberrations in sarcomas and breast cancers from Nf1 mutant mice, and tumor cell lines showed deregulated Ras signaling. Nf1(+/-) mice provide a tractable model for investigating the pathogenesis of common mutagen-induced cancers and for testing preventive strategies.
Chao
Richard C
RC
Department of Pediatrics, University of California, San Francisco, San Francisco, California 94143, USA.
Pyzel
Urszula
U
Fridlyand
Jane
J
Kuo
Yien-Ming
YM
Teel
Lewis
L
Haaga
Jennifer
J
Borowsky
Alexander
A
Horvai
Andrew
A
Kogan
Scott C
SC
Bonifas
Jeannette
J
Huey
Bing
B
Jacks
Tyler E
TE
Albertson
Donna G
DG
Shannon
Kevin M
KM
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000633:toxicity*; D003520:Cyclophosphamide / Q000633:toxicity*; D016514:Genes, Neurofibromatosis 1; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000209:etiology*; D009693:Nucleic Acid Hybridization; D010641:Phenotype; D011878:Radiotherapy / Q000009:adverse effects*
D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide