Abstract
The insulin-like growth factor (IGF) 1 receptor (IGF1R) is an important therapeutic target under study in many cancers. Here, we describe a breast cancer model based on expression of the ETV6-NTRK3 (EN) chimeric tyrosine kinase that suggests novel therapeutic applications of IGF1R inhibitors in secretory breast cancers. Originally discovered in congenital fibrosarcomas with t(12;15) translocations, EN was identified subsequently in secretory breast carcinoma (SBC) which represent a variant of invasive ductal carcinoma. Because fibroblast transformation by EN requires the IGF1R axis, we hypothesized a similar dependency may exist in mammary cells and, if so, that IGF1R inhibitors might be useful to block EN-driven breast oncogenesis. In this study, we analyzed EN expressing murine and human mammary epithelial cell lines for transformation properties. Various IGF1R signaling inhibitors, including the dual specificity IGF1R/insulin receptor (INSR) inhibitor BMS-536924, were then tested for effects on three-dimensional Matrigel cell growth, migration, and tumor formation. We found that EN expression increased acinar size and luminal filling in Matrigel cultures and promoted orthotopic tumor growth in mice. Tumors were well differentiated and nonmetastatic, similar to human SBC. The known EN effector pathway, PI3K-Akt, was activated in an IGF1- or insulin-dependent manner. BMS-536924 blocked EN transformation in vitro, whereas BMS-754807, another IGIFR/INSR kinase inhibitor currently in clinical trials, significantly reduced tumor growth in vivo. Importantly, EN model systems mimic the clinical phenotype observed in human SBC. Moreover, EN has a strict requirement for IGF1R or INSR in breast cell transformation. Thus, our findings strongly encourage the evaluation of IGF1R/INSR inhibitors to treat EN-driven breast cancers.
Highlights
The IGF1R signaling axis is emerging as an essential pathway for many cancers, including breast carcinoma, and inhibitors of this pathway are in various stages of clinical development
Our results indicate an essential role for IGF1R in EN breast cell oncogenesis
Our understanding of the role of oncogenic fusions in epithelial tumors has increased in recent years [41], identification of the ETV6-NTRK3 gene fusion as a primary genetic event in secretory breast carcinoma (SBC) [22] remains the only known example of a dominantly acting oncogene in human breast carcinoma
Summary
The IGF1R signaling axis is emerging as an essential pathway for many cancers, including breast carcinoma, and inhibitors of this pathway are in various stages of clinical development. IGF1R is normally activated by insulin-like growth factors 1 and 2 (IGF1 and IGF2), which trigger a Authors' Affiliations: 1Department of Molecular Oncology, BC Cancer Research Center; 2Department of Cellular and Physiological Sciences, University of British Columbia, Vancouver, British Columbia, Canada; 3Oncology Drug Discovery, Bristol-Myers Squibb Co, Princeton, New Jersey; and 4Lady Davis Institute for Medical Research SMBD, Jewish General Hospital, Montreal, Quebec, Canada. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). C.E. Tognon and A.M. Somasiri contributed to this work.
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