title: CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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 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(+) breast cancer and indicate the potential of novel therapies targeting CCL2 and CCL5 pathways.
authors.affiliation: Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Susanne
authors.initials: S
authors.lastname: Svensson
authors.affiliation: Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Annelie
authors.initials: A
authors.lastname: Abrahamsson
authors.affiliation: Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Gabriela Vazquez
authors.initials: GV
authors.lastname: Rodriguez
authors.affiliation: Department of Medical Biochemistry and Microbiology, Uppsala Biomedical Center, Uppsala University, Uppsala, Sweden.
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Olsson
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden. Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden.
authors.forename: Lasse
authors.initials: L
authors.lastname: Jensen
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden. Department of Medicine and Health Sciences, Linköping University, Linköping, Sweden. Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom.
authors.forename: Yihai
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden. charlotta.dabrosin@liu.se.
authors.forename: Charlotta
authors.initials: C
authors.lastname: Dabrosin
mesh_terms: D000818:Animals; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018932:Chemokine CCL2 / Q000096:biosynthesis* / Q000235:genetics; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D004958:Estradiol / Q000008:administration & dosage; D047628:Estrogen Receptor alpha / Q000096:biosynthesis / Q000235:genetics*; D004967:Estrogens / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D013629:Tamoxifen / Q000008:administration & dosage; D015027:Zebrafish
chemical_list: C111835:CCL2 protein, human; C483024:CCL5 protein, human; D018932:Chemokine CCL2; D018946:Chemokine CCL5; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D013629:Tamoxifen; D004958:Estradiol