Igf1r as a therapeutic target in a mouse model of basal-like breast cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (7), p.2359-2364
• Main Authors: Klinakis, Apostolos, Szabolcs, Matthias, Chen, Guoying, Xuan, Shouhong, Hibshoosh, Hanina, Efstratiadis, Argiris
• Format: Article
• Language: English
• Subjects: Animals; Biological Sciences; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - therapy; Cancer; Cell lines; Cells; Chemotherapy; Disease Models, Animal; Epithelial cells; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunophenotyping; Mammary glands; Mice; Mice, Transgenic; Models, Biological; Mouse mammary tumor virus; Podophyllotoxin - analogs & derivatives; Podophyllotoxin - pharmacology; ras Proteins - metabolism; Receptor, IGF Type 1 - metabolism; Receptors; Rodents; Signal Transduction; Squamous cell carcinoma; Stem cells; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0810221106

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 KrasG¹²D). 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 ([almost equal to]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 KRASG¹³D mutation.