Subtype-specific role for Jagged1 in promoting or inhibiting breast tumor formation

Area of Science:

• Oncology
• Developmental Biology
• Cell Signaling

Background:

• Notch signaling plays complex roles in breast cancer, with both tumor-suppressive and oncogenic functions.
• The specific role of Jagged1, a key Notch ligand in the mammary gland, remains unclear.

Purpose of the Study:

• To investigate the function of Jagged1 in mammary gland development and breast cancer.
• To determine the impact of Jagged1 deletion on mammary stem cells, differentiation, and tumor formation in different subtypes.

Main Methods:

• Deletion of Jagged1 in mammary epithelial cells of virgin and pregnant mice.
• Analysis of mammary stem cell (MaSC) compartment, luminal differentiation (progesterone receptor expression), and alveolar development.
• Assessment of mouse mammary tumor formation from luminal and basal cells.
• Correlation of Jagged1, HEY1, and HEY2 expression with patient survival in luminal and basal breast cancer subtypes.

Main Results:

• Jagged1 deletion in virgin mice expanded MaSCs and impaired luminal differentiation.
• Jagged1 deletion did not affect differentiation or involution in pregnant mice.
• Jagged1 deletion promoted luminal breast cancer but suppressed basal breast cancer.
• Downregulation of Notch target genes Hey1 (luminal) and Hey2 (basal) was observed.
• High JAG1/HEY1 expression correlated with better survival in luminal tumors; high JAG1/HEY2 correlated with worse survival in basal tumors.

Conclusions:

• Jagged1 is a critical regulator of mammary epithelial hierarchy.
• Jagged1-mediated Notch signaling has distinct roles in luminal and basal breast cancer subtypes.
• Jagged1 expression patterns predict patient survival outcomes in different breast cancer subtypes.