title: IGF1R inhibition in mammary epithelia promotes canonical Wnt signaling and Wnt1-driven tumors.
abstract: Triple-negative breast cancer (TNBC) is an aggressive disease subtype that, unlike other subtypes, lacks an effective targeted therapy. Inhibitors of the insulin-like growth factor receptor (IGF1R) have been considered for use in treating TNBC. Here, we provide genetic evidence that IGF1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt1 and mutant Igf1r, a reduction in IGF1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamous phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29(hi)/CD24(+)) and luminal (CD24(+)/CD61+/CD29(lo)) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacologic inhibition of the IGF1R in vitro was sufficient to increase the tumorsphere-forming efficiency ofMMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor versus the IR-B isoform, which when stimulated in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors, an attenuation of IGF1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes with potential implications for understanding TNBC pathobiology and treatment.
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Rota
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: Lidia
authors.initials: L
authors.lastname: Albanito
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: Marcus E
authors.initials: ME
authors.lastname: Shin
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: Corey L
authors.initials: CL
authors.lastname: Goyeneche
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: Sain
authors.initials: S
authors.lastname: Shushanov
authors.affiliation: Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Icahn Sinai School of Medicine at Mt. Sinai, New York, New York.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Gallagher
authors.affiliation: Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Icahn Sinai School of Medicine at Mt. Sinai, New York, New York.
authors.forename: Derek
authors.initials: D
authors.lastname: LeRoith
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Lazzarino
authors.affiliation: Department of Neurology and Neuroscience, New Jersey Medical School Cancer Center, Rutgers Biomedical and Health Sciences, Newark, New Jersey. terri.wood@rutgers.edu.
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Wood
mesh_terms: D000818:Animals; D005260:Female; D008175:Lung Neoplasms / Q000556:secondary; D008321:Mammary Glands, Animal / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction; D051155:Wnt1 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051155:Wnt1 Protein; D017526:Receptor, IGF Type 1
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