Biology of Human Tumors CCL2 andCCL5AreNovel Therapeutic Targets for Estrogen-Dependent Breast Cancer

Purpose: Novel therapeutic targets of estrogen receptor (ER)– positive breast cancers are urgently needed because current antiestrogen therapy causes severe adverse effects, nearly 50% of patients are intrinsically resistant, and the majority of recurrences have maintained ER expression. We investigated the role of estrogen-dependent chemokine expression and subsequent cancer growth in human tissues and experimental breast cancer models. Experimental Design: For in vivo sampling of human chemokines, microdialysis was used in breast cancers of women or normal human breast tissue before and after tamoxifen therapy. Estrogen exposure and targeted therapies were assessed in immune competent PyMT murine breast cancer, orthotopic human breast cancers in nude mice, cell culture of cancer cells, and freshly isolated human macrophages. Cancer cell dissemination was investigated using zebrafish. Results: ERþ cancers in women produced high levels of extracellular CCL2 and CCL5 in vivo, which was associated with infiltration of tumor-associated macrophages. In experimental breast cancer, estradiol enhanced macrophage influx and angiogenesis through increased release of CCL2, CCL5, and vascular endothelial growth factor. These effects were inhibited by antiCCL2or anti-CCL5 therapy,which resulted inpotent inhibitionof cancer growth. In addition, estradiol induced a protumorigenic activationof themacrophages. In a zebrafishmodel,macrophages increased cancer cell dissemination via CCL2 and CCL5 in the presence of estradiol, which was inhibited with anti-CCL2 and anti-CCL5 treatment. Conclusions:Our findings shed new light on the mechanisms underlying the progression of ERþ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways. Clin Cancer Res; 21(16); 3794–805. 2015 AACR.