Promotion of the invasion and metastasis of breast cancer by B7-H3 through CCR5High tumor-associated macrophages.

Breast cancer (BC) ranks first in morbidity and second in mortality in all female cancers, and previous studies support the contribution of tumor-associated macrophages (TAMs) to cancer progression. B7-H3 is aberrantly expressed in a variety of solid cancers, and may also promote cancer progression, but its function is still yet to be known. In this study, the importance of B7-H3 in BC pathogenesis was investigated through TAM. The expression of B7-H3 and CCR5 on macrophages/monocytes was first detected in 135 human BC tissues and peripheral blood by flow cytometry. In the tumor microenvironment, the expression of B7-H3 on TAM was positively correlated with CCR5 levels on TAM. Clinical analysis indicated that CCR5^high TAM was significantly correlated with the size of tumors (T) (P = 0 .011) and E-cadherin (P < 0.0001). In vitro, knockdown of B7-H3 reduced the expression of CCL3/4 on a cell line of monocytes THP-1. Further studies showed that B7-H3 could recruit TAMs through the CCL3/4-CCR5 axis, and that CCR5^highTAM recruited in the tumor microenvironment could enhance BC migration and invasion. In addition, B7-H3 and CCR5 can facilitate the EMT process through the MAPK/ERK and NF-ΚB pathways. In conclusion, it is speculated that B7-H3 may regulate CCR5^high TAMs through the CCL3/4-CCR5 axis, thereby promoting BC migration and invasion.