CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer

Abstract

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 anti-CCL2 or anti-CCL5 therapy, which resulted in potent inhibition of cancer growth. In addition, estradiol induced a protumorigenic activation of the macrophages. In a zebrafish model, 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 ER þ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways.

Estradiol Promotes Breast Cancer Cell Migration via Recruitment and Activation of Neutrophils

“…The zebrafish metastasis model allows for such investigation (10,31). By using this model, we showed here that neutrophils increased ER þ breast cancer cell dissemination, which is in agreement with recent published data (7).…”

“…We have previously shown that E 2 does not affect the number of neutrophils in central tumor tissues and that the numbers of neutrophils in the centers of tumors are very low (10). Our present data suggest that neutrophils are preferentially localized in the invasive margin and that E 2 significantly affects the number of these neutrophils both in immune-competent and immune-deficient mouse models of breast cancer.…”

“…Several types of immune cells express the ER, and estrogen affects the expression of inflammatory mediators in neutrophils and macrophages (8,9). We have shown that estrogen increases the influx of macrophages into breast cancers and induces a protumorigenic phenotype (M2) in these cells (10).…”

Relationship of the Breast Ductal Carcinoma In Situ Immune Microenvironment with Clinicopathological and Genetic Features

“…In our cohort of pure DCIS, we identified associations between It is not yet conclusively known why some breast carcinomas have higher TILs than others. Polarization toward an immunosuppressive microenvironment due to ER signaling has been suggested as one possibility to explain elevated TILs in ER-negative carcinomas (35). Another is the relationship with genetic aberrations, as in melanoma, because the overall mutational load is much higher in triple-negative than luminal subtype breast carcinomas, with higher potential for neoantigen formation (36).…”

Dense breast tissue in postmenopausal women is associated with a pro-inflammatory microenvironment in vivo

“…We have previously shown increased extracellular in vivo levels of several inflammatory mediators, such as interleukin (IL)-1, IL-8, chemokine (C-C motif) ligand (CCL) 2, CCL5, leptin, and vascular endothelial growth factor (VEGF) in breast cancers of women and an association with sex steroids of these factors in normal human breast tissue. [4][5][6][7][8][9][10][11][12] Mammographic density has been associated with increased risk of breast cancer. 13 In a meta-analysis women with >75% dense breast area have a 4-fold increased risk of developing breast cancer compared to women with <5% dense breast area.…”