Igf1r as a therapeutic target in a mouse model of basal-like breast cancer.
Considering the strong association between dysregulated insulin-like growth factor (IGF) signaling and various human cancers, we have used an expedient combination of genetic analysis and pharmacological treatment to evaluate the potential of the type 1 IGF receptor (Igf1r) for targeted anticancer therapy in a mouse model of mammary tumorigenesis. In this particular strain of genetically modified animals, histopathologically heterogeneous invasive carcinomas exhibiting up-regulation of the Igf1r gene developed extremely rapidly by mammary gland-specific overexpression of constitutively active oncogenic Kras* (mutant Kras(G12D)). Immunophenotyping data and expression profiling analyses showed that, except for a minor luminal component, these mouse tumors resembled basal-like human breast cancers. This is a group of aggressive tumors of poor prognosis for which there is no targeted therapy currently available, and it includes a subtype correlating with KRAS locus amplification. Conditional ablation of Igf1r in the mouse mammary epithelium increased the latency of Kras*-induced tumors very significantly (approximately 11-fold in comparison with the intact model), whereas treatment of tumor-bearing animals by administration of picropodophyllin (PPP), a specific Igf1r inhibitor, resulted in a dramatic decrease in tumor mass of the main forms of basal-like carcinomas. PPP also was effective against xenografts of the human basal-like cancer cell line MDA-MB-231, which carries a KRAS(G13D) mutation.
Klinakis
Apostolos
A
Department of Genetics and Development, Columbia University, 1150 St. Nicholas Avenue, New York, NY 10032, USA.
Szabolcs
Matthias
M
Chen
Guoying
G
Xuan
Shouhong
S
Hibshoosh
Hanina
H
Efstratiadis
Argiris
A
D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism* / Q000628:therapy*; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D011034:Podophyllotoxin / Q000031:analogs & derivatives / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D015398:Signal Transduction; D018631:ras Proteins / Q000378:metabolism
C415032:picropodophyllin; D017526:Receptor, IGF Type 1; D018631:ras Proteins; D011034:Podophyllotoxin