Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation. Neoplasia 2020 Nov;22(11):644-658
Date
10/20/2020Pubmed ID
33070870Pubmed Central ID
PMC7573506DOI
10.1016/j.neo.2020.07.001Scopus ID
2-s2.0-85088218084 (requires institutional sign-in at Scopus site) 11 CitationsAbstract
Fbw7 is a tumor suppressor that regulates the degradation of oncogenic substrates such as c-Jun, c-Myc, Notch1 intracellular domain (ICD), and cyclin E by functioning as the substrate recognition protein in the Skp1-Cullin-F-box (SCF) ubiquitin ligase complex. Consequently, low expression or loss of FBXW7 in breast cancer has been hypothesized to result in the accumulation of oncogenic transcription factors that are master regulators of proliferation, apoptosis, and ultimately transformation. Despite this, the direct effect of Fbw7 loss on mammary gland morphology and tumorigenesis has not been examined. Here, we demonstrate that conditional deletion of Fbxw7 in murine mammary tissue initiates breast tumor development and also results in lactation and involution defects. Further, while Fbxw7 loss results in the overexpression of Notch1-ICD, c-Jun, cyclin E, and c-Myc, the downstream transcription factor pathways associated with c-Myc and cyclin E are the most dysregulated, including at the single-cell level. These pathways are dysregulated early after Fbxw7 loss, and their sustained loss results in tumorigenesis and reinforced c-Myc and cyclin E-E2F pathway disruption. We also find that loss of Fbxw7 is linked to the acquisition of Trp53 mutations, similar to the mutational spectrum observed in patients. Our results demonstrate that the loss of Fbxw7 promotes the acquisition of Trp53 mutations and that the two cooperate in breast tumor development. Targeting c-Myc, E2F, or p53 may therefore be a beneficial treatment strategy for FBXW7-altered breast cancer patients.
Author List
Meyer AE, Furumo Q, Stelloh C, Minella AC, Rao SAuthor
Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAnimals
Breast Neoplasms
Cell Line, Tumor
Cell Transformation, Neoplastic
Disease Models, Animal
Disease Susceptibility
E2F Transcription Factors
F-Box-WD Repeat-Containing Protein 7
Female
Gene Expression Regulation, Neoplastic
Immunohistochemistry
Mice
Mice, Knockout
Mice, Transgenic
Mutation
Proto-Oncogene Proteins c-myc
Transcription, Genetic
Tumor Suppressor Protein p53
