Insight into mammary gland development and tumor progression in an E2F5 conditional knockout mouse model

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Breast cancer development is linked to disrupted mammary gland development.
• E2F transcription factors (E2F1-4) have known roles in mammary development, but E2F5's function is largely unknown.
• Understanding normal mammary development can elucidate mechanisms of malignant transformation.

Purpose of the Study:

• To investigate the role of E2F5 in mammary gland development and function.
• To determine if E2F5 loss contributes to mammary tumor formation and metastasis.
• To identify molecular pathways affected by E2F5 deficiency in the mammary gland.

Main Methods:

• Single-cell RNA sequencing (scRNAseq) to detect E2F5 expression and activity.
• Generation of a mammary-specific E2F5 conditional knockout mouse model.
• Whole genome sequencing, RNA sequencing, and protein analysis of tumors.
• Tumor transplantation studies in immunocompetent recipients.

Main Results:

• E2F5 is present in the mammary gland and its activity changes during development.
• Mammary-specific E2F5 knockout mice developed highly metastatic mammary tumors after a prolonged latency.
• Significant intertumor heterogeneity was observed.
• Altered Cyclin D1 levels were identified, similar to MMTV-Neu tumors, suggesting Cyclin D1 dependency.
• Tumor cells metastasized to lymph nodes.

Conclusions:

• Loss of E2F5 promotes the development of metastatic mammary tumors, potentially via altered Cyclin D1 regulation.
• E2F5 functions as a tumor suppressor in the mammary gland by regulating a gene network.
• Conditional E2F5 loss in the mammary gland is sufficient to induce tumor formation and metastasis.