Preneoplastic changes persist after IGF-IR downregulation and tumor regression

Abstract

Despite our incomplete understanding of the function of the type I insulin-like growth factor receptor (IGF-IR) in tumorigenesis, IGF-IR targeting agents have entered clinical trials for the treatment of human cancers. Previously, we have shown that downregulation of IGF-IR transgene in mammary tumors in MTB-IGFIR transengic mice results in tumor regression in a majority of the mice and most of these mice do not develop recurrent mammary tumors. In this study, we examined mammary tissue of mice that did not develop recurrent tumors. Areas of tumor regression were visible macroscopically and microscopically these lesions contained cell debris, individual cells, lipofuscin and doxycycline crystals. Three of the 12 mice also presented with considerable lobuloalveolar development. The re-expression of the IGF-IR transgene in mammary tissue with stably regressed tumors resulted in the rapid re-emergence of mammary tumors, some of which seemed to originate from the regressed mammary lesions. Thus, despite stable tumor regression after IGF-IR downregulation, mammary tissue contained preneoplastic lesions and tumors rapidly re-appear upon re-overexpression of IGF-IR transgene. Therefore, IGF-IR-targeting agents may be effective at regressing mammary tumors expressing IGF-IR, but these agents will not completely eradicate all tumor cells or restore the mammary stromal environment.