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CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer
Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology. Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences.
Uppsala University, Sweden.
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2015 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 21, no 16, 3794-3805 p.Article in journal (Refereed) Published
Abstract [en]

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: 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. (C)2015 AACR.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2015. Vol. 21, no 16, 3794-3805 p.
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Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-122122DOI: 10.1158/1078-0432.CCR-15-0204ISI: 000361909100027PubMedID: 25901081OAI: oai:DiVA.org:liu-122122DiVA: diva2:861767
Note

Funding Agencies|Swedish Cancer Society [2009/799]; Swedish Research Council [2010-3458]; LiU-Cancer; Linkoping University Hospital

Available from: 2015-10-19 Created: 2015-10-19 Last updated: 2016-04-25

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Svensson, SusanneAbrahamsson, AnnelieJensen, LasseCao, YihaiDabrosin, Charlotta
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Department of OncologyDivision of Clinical SciencesFaculty of Medicine and Health SciencesDivision of Cardiovascular Medicine
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Clinical Cancer Research
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