title: ETV6-NTRK3-mediated breast epithelial cell transformation is blocked by targeting the IGF1R signaling pathway.
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.
authors.affiliation: Department of Molecular Oncology, BC Cancer Research Center, Vancouver, British Columbia, Canada.
authors.forename: Cristina E
authors.initials: CE
authors.lastname: Tognon
authors.forename: Aruna M
authors.initials: AM
authors.lastname: Somasiri
authors.forename: Valentina E
authors.initials: VE
authors.lastname: Evdokimova
authors.forename: Genny
authors.initials: G
authors.lastname: Trigo
authors.forename: Evett E
authors.initials: EE
authors.lastname: Uy
authors.forename: Nataliya
authors.initials: N
authors.lastname: Melnyk
authors.forename: Joan M
authors.initials: JM
authors.lastname: Carboni
authors.forename: Marco M
authors.initials: MM
authors.lastname: Gottardis
authors.forename: Calvin D
authors.initials: CD
authors.lastname: Roskelley
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Poul H B
authors.initials: PH
authors.lastname: Sorensen
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D051058:Oncogene Protein v-akt / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis*; D011728:Pyridones / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D020812:Receptor, trkC; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D001562:Benzimidazoles; D055504:Insulin Receptor Substrate Proteins; D051058:Oncogene Protein v-akt; D015514:Oncogene Proteins, Fusion; D011728:Pyridones; D017526:Receptor, IGF Type 1; C504983:BMS 536924; C484319:ETV6-NTRK3 fusion protein, human; D020812:Receptor, trkC; D000097764:ETS Translocation Variant 6 Protein; C526292:IRS1 protein, human