c-Jun induces mammary epithelial cellular invasion and breast cancer stem cell expansion

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Breast tumor self-renewal mechanisms are critical for cancer progression and treatment resistance.
• ErbB2 oncogene overexpression occurs in ~30% of human breast cancers.
• c-Jun, a proto-oncogene, is also overexpressed in breast cancer, but its role is unclear.

Purpose of the Study:

• To investigate the role of endogenous c-Jun in mammary tumor progression, invasion, and stem cell function.
• To elucidate the molecular mechanisms by which c-Jun influences ErbB2-induced mammary tumors.

Main Methods:

• Generation of transgenic mice by crossing ErbB2-expressing mice with c-jun(f/f) mice.
• Utilized Cre recombinase for c-jun gene excision.
• Performed proteomic analysis to identify secreted proteins.
• Assessed cellular migration, invasion, and mammosphere formation.

Main Results:

• Excision of c-jun significantly reduced migration, invasion, and mammosphere formation in ErbB2-induced tumors.
• Proteomic analysis revealed ErbB2-induced expression of stem cell factor (SCF) and CCL5, dependent on c-Jun.
• c-Jun transcriptionally induced SCF and CCL5.
• CCL5 rescued c-Jun-deficient tumor cell invasion, and SCF rescued mammosphere production.

Conclusions:

• Endogenous c-Jun plays a crucial role in ErbB2-induced mammary tumor cell invasion.
• c-Jun is essential for self-renewal in these tumors, partly through transcriptional regulation of SCF and CCL5.
• Targeting c-Jun may offer a therapeutic strategy for ErbB2-positive breast cancers.