PUBLICATION
CCL2 and CCL5 are novel therapeutic targets for estrogen-dependent breast cancer
- Authors
- Svensson, S., Abrahamsson, A., Vazquez Rodriguez, G., Olsson, A.K., Jensen, L., Cao, Y., Dabrosin, C.
- ID
- ZDB-PUB-150423-3
- Date
- 2015
- Source
- Clinical cancer research : an official journal of the American Association for Cancer Research 21(16): 3794-805 (Journal)
- Registered Authors
- Keywords
- Microdialysis, Estradiol, Tamoxifen, Zebrafish, Macrophages
- MeSH Terms
-
- Animals
- Breast/drug effects
- Breast/pathology
- Breast Neoplasms/drug therapy
- Breast Neoplasms/genetics*
- Breast Neoplasms/pathology
- Chemokine CCL2/biosynthesis*
- Chemokine CCL2/genetics
- Chemokine CCL5/biosynthesis*
- Chemokine CCL5/genetics
- Disease Models, Animal
- Estradiol/administration & dosage
- Estrogen Receptor alpha/biosynthesis
- Estrogen Receptor alpha/genetics*
- Estrogens/genetics
- Estrogens/metabolism
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Macrophages/metabolism
- Macrophages/pathology
- Mice
- Mice, Nude
- Molecular Targeted Therapy
- Neoplasms, Experimental/drug therapy
- Neoplasms, Experimental/genetics*
- Neoplasms, Experimental/pathology
- Neovascularization, Pathologic/drug therapy
- Neovascularization, Pathologic/genetics*
- Neovascularization, Pathologic/pathology
- Tamoxifen/administration & dosage
- Zebrafish
- PubMed
- 25901081 Full text @ Clin. Cancer Res.
Citation
Svensson, S., Abrahamsson, A., Vazquez Rodriguez, G., Olsson, A.K., Jensen, L., Cao, Y., Dabrosin, C. (2015) CCL2 and CCL5 are novel therapeutic targets for estrogen-dependent breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 21(16):3794-805.
Abstract
Purpose Novel therapeutic targets of estrogen receptor (ER)-positive breast cancers are urgently needed because current anti-estrogen 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 ER+ 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 pro-tumorigenic 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+ breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping