Abstract
Dedifferentiation programs are commonly enacted during breast cancer progression to enhance tumor cell fitness. Increased cellular plasticity within the neoplastic compartment of tumors correlates with disease aggressiveness, often culminating in greater resistance to cytotoxic therapies or augmented metastatic potential. Here, we found that subpopulations of dedifferentiated neoplastic breast epithelial cells express canonical leukocyte cell surface receptor proteins and have thus named this cellular program "immune mimicry." Analysis of public human breast tumor single-cell RNA-sequencing datasets and histopathological breast tumor specimens, as well as functional experiments in vitro in breast cancer cell lines and in vivo in murine transgenic and cell line-derived mammary cancer models, showed that neoplastic cells engaged in immune mimicry. Immune-mimicked neoplastic cells harbored hallmarks of dedifferentiation and were enriched in treatment-resistant and high-grade breast tumors. In aggressive breast cancer cell lines, anti-proliferative cytotoxic chemotherapies drove epithelial cells toward immune mimicry. Expression of the CD69 leukocyte activation protein by neoplastic cells conferred a proliferative advantage that facilitated early tumor growth. Together, these findings suggest that neoplastic breast epithelial cells upregulating leukocyte surface receptors potentiate malignancy and that neoplastic immune mimicry has potential clinical utility for patient prognosis and stratification.