Ancestry-linked stromal variations impact breast epithelial cell invasion

Breast cancer is a significant health challenge worldwide, and disproportionately affects women of African ancestry (AA) who experience higher mortality rates relative to other racial/ethnic groups. Several studies have pointed to biological factors that affect breast cancer outcomes. A recently discovered stromal cell population that expresses PROCR, ZEB1 and PDGFR (PZP cells) was found to be enriched in normal healthy breast tissue from AA donors, and only in tumor adjacent tissues from donors of European ancestry (EA). Here, we investigated the effect of PZP cells on the acquisition of tumorigenic phenotypes in AA and EA human breast epithelial cells to determine its contribution to the biological basis of outcome disparities. Using 3D cell models of tumor invasion, we find that PZP cells confer invasive capacity to epithelial cells independent of genetic ancestry, wherein cells exhibit leader-follower behaviors during extracellular matrix invasion. Enhanced epithelial invasion stems from a combination of AKT activation and fibronectin deposition by the PZP cells. Although activation of AKT in epithelial cells alone is insufficient to induce invasive behaviors, blocking AKT activation markedly reduces invasive capacity. These findings point to the germaneness of differences in breast biology and the multi-faceted roles and enrichment in PZP cells in AA breast tissue, in furthering current understanding of the molecular basis for worse prognosis for patients of African descent.