A Versatile Tumor Gene Deletion System Reveals a Crucial Role for FGFR1 in Breast Cancer Metastasis

RCAS avian viruses have been used to deliver oncogene expression and induce tumors in transgenic mice expressing the virus receptor TVA. Here we report the generation and characterization of a novel RCAS-Cre-IRES-PyMT (RCI-PyMT) virus designed to specifically knockout genes of interest in tumors generated in appropriate mutant mouse hosts. FGF receptor 1 (FGFR1) is a gene that is amplified in human breast cancer, but there have been no definitive studies on its function in mammary tumorigenesis, progression, and metastasis in vivo in spontaneous tumors in mice. We used the retroviral tumor knockout, or TuKO, strategy to delete fgfr1 in PyMT-induced mammary tumors in K19-tva/fgfr1(loxP/loxP) mice. The similarly injected control K19-tva mice developed mammary tumors exhibiting high metastasis to lung, making this an ideal model for breast cancer metastasis. The fgfr1 TuKO tumors showed significantly decreased primary tumor growth and, most importantly, greatly reduced metastasis to lung. In contrast to previous reports, FGFR1 action in this spontaneous mammary tumor model does not significantly induce epithelial-to-mesenchymal transition. Loss of FGFR1 does generate a gene signature that is reverse correlated with FGFR1 gene amplification and/or upregulation in human breast cancer. Our results suggest that FGFR1 signaling is a key pathway driving breast cancer lung metastasis and that targeting FGFR1 in breast cancer is an exciting approach to inhibit metastasis.