Loss of Fbxw7 triggers mammary tumorigenesis associated with E2F/c-Myc activation and Trp53 mutation

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Fbw7 acts as a tumor suppressor by degrading oncogenic proteins like c-Myc and Notch1.
• FBXW7 loss in breast cancer is hypothesized to drive tumorigenesis by accumulating these oncoproteins.
• The direct impact of Fbw7 loss on mammary gland development and cancer has not been fully elucidated.

Purpose of the Study:

• To investigate the direct role of Fbw7 loss in murine mammary gland morphology and tumorigenesis.
• To identify the specific downstream pathways dysregulated by Fbw7 loss.
• To explore the relationship between Fbw7 loss, p53 mutations, and breast cancer development.

Main Methods:

• Conditional deletion of Fbxw7 in mouse mammary tissue.
• Analysis of mammary gland morphology, lactation, and involution.
• Assessment of oncogenic substrate levels (Notch1-ICD, c-Jun, cyclin E, c-Myc).
• Single-cell level analysis of downstream transcription factor pathways.
• Examination of Trp53 mutation acquisition.

Main Results:

• Conditional Fbxw7 deletion initiated breast tumor development and caused lactation/involution defects.
• Fbxw7 loss led to overexpression of Notch1-ICD, c-Jun, cyclin E, and c-Myc.
• Dysregulation of c-Myc and cyclin E-E2F pathways occurred early and persisted, driving tumorigenesis.
• Fbxw7 loss was linked to the acquisition of Trp53 mutations, cooperating in tumor development.

Conclusions:

• Fbw7 loss promotes breast tumorigenesis through the dysregulation of c-Myc and cyclin E pathways.
• Fbw7 loss cooperates with Trp53 mutations in breast cancer development.
• Targeting c-Myc, E2F, or p53 pathways may offer therapeutic strategies for FBXW7-altered breast cancers.