Journal
CANCER RESEARCH
Volume 74, Issue 19, Pages 5668-5679Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-14-0970
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Funding
- National Institute of Diabetes, Digestive and Kidney Diseases [DK60612]
- Ruth Estrin Goldberg Foundation
- NJCCR [DFHS12CRP011]
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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 beta-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 of MMTV-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 beta-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. (C) 2014 AACR.
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