Ancestry-linked stromal variations impact breast epithelial cell invasion

Area of Science:

• Oncology
• Cell Biology
• Genetics

Background:

• Breast cancer disproportionately affects women of African ancestry (AA), leading to higher mortality rates compared to European ancestry (EA) populations.
• Stromal cell populations, including those expressing P ROCR, ZEB1, and PDGFRα (PZP cells), are implicated in breast cancer progression.
• PZP cells are enriched in normal AA breast tissue and tumor-adjacent EA breast tissue, suggesting a role in ancestry-related disparities.

Purpose of the Study:

• To investigate the impact of PZP cells on the tumorigenic phenotypes of AA and EA human breast epithelial cells.
• To determine the contribution of PZP cells to the biological basis of breast cancer outcome disparities.
• To elucidate the mechanisms by which PZP cells influence breast cancer invasion.

Main Methods:

• Utilized 3D cell models to simulate tumor invasion in vitro.
• Co-cultured human breast epithelial cells with PZP cells derived from different ancestries.
• Analyzed cellular behaviors, including extracellular matrix invasion and leader-follower dynamics.
• Investigated the roles of AKT signaling pathway activation and fibronectin deposition.

Main Results:

• PZP cells conferred invasive capacity to breast epithelial cells independently of genetic ancestry.
• Observed leader-follower behaviors during extracellular matrix invasion mediated by PZP cells.
• Enhanced invasion resulted from a combination of AKT activation and fibronectin deposition by PZP cells.
• Blocking AKT activation significantly reduced the invasive capacity of epithelial cells.

Conclusions:

• PZP cells play a crucial role in promoting breast cancer cell invasion through AKT activation and fibronectin deposition.
• The enrichment of PZP cells in AA breast tissue may contribute to the observed disparities in breast cancer prognosis.
• Understanding the role of PZP cells offers insights into the molecular basis of breast cancer outcome differences across ancestries.