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Published on: May 20, 2015
CCL2 and CCL5 Are Novel Therapeutic Targets for Estrogen-Dependent Breast Cancer
Susanne Svensson1, Annelie Abrahamsson1, Gabriela Vazquez Rodriguez1
1Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
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.
Insights
Estrogen receptor-positive breast cancers utilize chemokines CCL2 and CCL5 to promote tumor growth and spread. Targeting these pathways with novel therapies may offer new treatment options for patients.
Area of Science:
- Oncology
- Immunology
- Endocrinology
Background:
- Estrogen receptor-positive (ER+) breast cancer remains a significant health challenge, with limited treatment options and high rates of resistance and recurrence.
- Current antiestrogen therapies for ER+ breast cancer are associated with severe adverse effects and limited efficacy in a substantial portion of patients.
- Understanding the mechanisms driving ER+ breast cancer progression is crucial for developing more effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of estrogen-dependent chemokine expression in the growth and dissemination of ER+ breast cancer.
- To explore the potential of targeting chemokine pathways as a novel therapeutic approach for ER+ breast cancer.
Main Methods:
- Microdialysis was employed to sample chemokines in human breast cancer tissues before and after tamoxifen therapy.
- Experimental models, including immune-competent murine breast cancer, orthotopic human breast cancers in nude mice, and zebrafish, were used to assess estrogen's effects and targeted therapies.
- In vitro studies involved cell cultures of cancer cells and analysis of freshly isolated human macrophages.
Main Results:
- Estrogen receptor-positive (ER+) breast cancers in women exhibited high in vivo production of CCL2 and CCL5, correlating with tumor-associated macrophage infiltration.
- Estradiol promoted macrophage influx and angiogenesis in experimental models by increasing CCL2, CCL5, and vascular endothelial growth factor release.
- Therapies targeting CCL2 or CCL5 potently inhibited tumor growth and reduced cancer cell dissemination in both murine and zebrafish models, with estradiol inducing protumorigenic macrophage activation.
Conclusions:
- Estrogen signaling drives ER+ breast cancer progression through chemokine-mediated mechanisms involving CCL2 and CCL5.
- Targeting the CCL2 and CCL5 pathways represents a promising novel therapeutic strategy for ER+ breast cancer.
- These findings offer new insights into the complex interplay between estrogen, chemokines, and immune cells in breast cancer development.
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