Loss of Fbxw7 Impairs Development of and Induces Heterogeneous Tumor Formation in the Mouse Mammary Gland

Abstract

Fbxw7 is an F-box protein that contributes to regulation of cell proliferation and cell fate determination as well as to tumor suppression in various tissues. In this study, we generated mice with mammary gland-specific ablation of Fbxw7 (Blg-Cre/Fbxw7F/F mice) and found that most neonates born to mutant dams die soon after birth as a result of defective maternal lactation. The mammary gland of mutant dams was markedly atrophic and manifested both excessive cell proliferation and apoptosis in association with the accumulation of Notch1 and p63. Despite the hypoplastic nature of the mutant mammary gland, Blg-Cre/Fbxw7F/F mice spontaneously developed mammary tumors that resembled basal-like carcinoma with marked intratumoral heterogeneity. Additional inactivation of Trp53 in Blg-Cre/Fbxw7F/F mice further promoted onset and development of mammary tumors, suggesting that spontaneous mutation of Trp53 may facilitate transition of hypoplastic mammary lesions to aggressive cancer in mice lacking Fbxw7. RNA-sequencing analysis of epithelial- and mesenchymal-like cell lines from a Blg-Cre/Fbxw7F/F mouse tumor revealed an increased mutation rate and structural alterations in the tumor and differential expression of upstream transcription factors including known targets of Fbxw7. Together, our results implicate Fbxw7 in the regulation of cell differentiation and in tumor suppression in the mammary gland. Loss of Fbxw7 increases mutation rate and chromosome instability, activates signaling pathways governed by transcription factors regulated by Fbxw7, and triggers the development of mammary tumors with prominent heterogeneity.