Schmidtmann Madison G, Elliott Victoria, Clancy James W, Schafer Zachary T, Nakshatri Harikrishna, D'Souza-Schorey Crislyn
Department of Biological Sciences, University of Notre Dame, Notre Dame, IN, USA.
Department of Surgery, Indiana University School of Medicine, and the VA Roudebush Medical Center, Indianapolis, IN, USA.
iScience. 2025 May 16;28(6):112686. doi: 10.1016/j.isci.2025.112686. eCollection 2025 Jun 20.
Breast cancer disproportionately affects women of African ancestry (AA) in part due to biological factors that affect disease outcome. A cell population that expresses PROCR, ZEB1, and PDGFRα (PZP) was recently found to be enriched in breast stroma from healthy AA donors, but only in tumor-adjacent tissues from donors of European ancestry (EA). Here, we show that PZP cells conferred invasive capacity to epithelial cells of both AA and EA origin in 3D cell models wherein cells exhibited leader-follower behaviors during extracellular matrix invasion. Epithelial cell invasion stemmed from a combination of AKT activation and fibronectin deposition by PZP cells. Although AKT activation in epithelial cells alone was insufficient to enhance invasion, blocking AKT activation markedly reduced invasive capacity. These findings point to the germaneness of intrinsic differences in normal breast tissues, such as PZP cell enrichment, in furthering understanding of the molecular basis for worse prognosis in patient cohorts.
乳腺癌对非洲裔（AA）女性的影响尤为严重，部分原因是影响疾病转归的生物学因素。最近发现，一种表达PROCR、ZEB1和PDGFRα（PZP）的细胞群体在健康AA供体的乳腺基质中富集，但仅在欧洲裔（EA）供体的肿瘤邻近组织中存在。在此，我们表明，在三维细胞模型中，PZP细胞赋予了源自AA和EA的上皮细胞侵袭能力，在这种模型中，细胞在细胞外基质侵袭过程中表现出引领-跟随行为。上皮细胞侵袭源于PZP细胞激活AKT和沉积纤连蛋白。虽然仅上皮细胞中的AKT激活不足以增强侵袭，但阻断AKT激活会显著降低侵袭能力。这些发现表明，正常乳腺组织中的内在差异（如PZP细胞富集）与进一步理解患者队列中预后较差的分子基础密切相关。
