Hdc-expressing myeloid-derived suppressor cells promote basal-like transition and metastasis of breast cancer

Metastases are the greatest contributors to death from breast cancer. Here, we identified a distinct subpopulation of luminal breast cancer characterized by cytokeratin 14 (CK14) expression in secondary colonies rather than primary tumors. This entity possessed a poorer prognosis compared to their CK14(-) counterparts. Immunohistochemical analysis showed that myeloid-derived suppressor cells (MDSCs) were recruited into the tumor microenvironment and exhibited a close spatial relationship with CK14(+) cancer cells. We demonstrated that histidine decarboxylase (Hdc) is capable of labeling myeloid-biased hematopoietic stem cell/progenitor cell (HSC/HSPC) and immature myeloid cells infiltrating in tumor tissues. FACS data obtained from Hdc-CreER(T2); eGFP; MMTV-PyVT female mice revealed an increased percentage of Hdc(+) PMN-MDSCs in metastatic masses. Hdc(+) PMN-MDSCs expressed high levels of canonical Wnts, including Wnt2, Wnt4, Wnt5a, and Wnt7b, to aberrantly activate Wnt/β-catenin signaling in CK14(+) malignant cells. β-catenin translocated from the membrane into the cytoplasm and nucleus. Targeted ablation of Hdc(+) PMN-MDSCs-derived Wnts through porcupine(flox/flox) and iDTR transgenic models hampered the metastatic cascade, making Hdc(+) immature myeloid cells an attractive candidate for tailed immunotherapies.