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Molecular Cancer Research
Molecular Cancer Research

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Oncogenes and Tumor Suppressors

CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation

Min Yao, Wei Fang, Curtis Smart, Qingting Hu, Shixia Huang, Nehemiah Alvarez, Patrick Fields and Nikki Cheng
Min Yao
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Wei Fang
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Curtis Smart
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Qingting Hu
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Shixia Huang
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas.
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Nehemiah Alvarez
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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  • ORCID record for Nehemiah Alvarez
Patrick Fields
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.
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Nikki Cheng
Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, Kansas.Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas.
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  • For correspondence: ncheng@kumc.edu
DOI: 10.1158/1541-7786.MCR-18-0750 Published February 2019
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Abstract

Basal-like breast cancers are an aggressive breast cancer subtype, which often lack estrogen receptor, progesterone receptor, and Her2 expression, and are resistant to antihormonal and targeted therapy, resulting in few treatment options. Understanding the underlying mechanisms that regulate progression of basal-like breast cancers would lead to new therapeutic targets and improved treatment strategies. Breast cancer progression is characterized by inflammatory responses, regulated in part by chemokines. The CCL2/CCR2 chemokine pathway is best known for regulating breast cancer progression through macrophage-dependent mechanisms. Here, we demonstrated important biological roles for CCL2/CCR2 signaling in breast cancer cells. Using the MCF10CA1d xenograft model of basal-like breast cancer, primary tumor growth was significantly increased with cotransplantation of patient-derived fibroblasts expressing high levels of CCL2, and was inhibited with CRISP/R gene ablation of stromal CCL2. CRISP/R gene ablation of CCR2 in MCF10CA1d breast cancer cells inhibited breast tumor growth and M2 macrophage recruitment and validated through CCR2 shRNA knockdown in the 4T1 model. Reverse phase protein array analysis revealed that cell-cycle protein expression was associated with CCR2 expression in basal-like breast cancer cells. CCL2 treatment of basal-like breast cancer cell lines increased proliferation and cell-cycle progression associated with SRC and PKC activation. Through pharmacologic approaches, we demonstrated that SRC and PKC negatively regulated expression of the cell-cycle inhibitor protein p27KIP1, and are necessary for CCL2-induced breast cancer cell proliferation.

Implications: This report sheds novel light on CCL2/CCR2 chemokine signaling as a mitogenic pathway and cell-cycle regulator in breast cancer cells.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Received July 16, 2018.
  • Revision received October 10, 2018.
  • Accepted November 12, 2018.
  • Published first November 16, 2018.
  • ©2018 American Association for Cancer Research.
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Molecular Cancer Research: 17 (2)
February 2019
Volume 17, Issue 2
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CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation
Min Yao, Wei Fang, Curtis Smart, Qingting Hu, Shixia Huang, Nehemiah Alvarez, Patrick Fields and Nikki Cheng
Mol Cancer Res February 1 2019 (17) (2) 604-617; DOI: 10.1158/1541-7786.MCR-18-0750

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CCR2 Chemokine Receptors Enhance Growth and Cell-Cycle Progression of Breast Cancer Cells through SRC and PKC Activation
Min Yao, Wei Fang, Curtis Smart, Qingting Hu, Shixia Huang, Nehemiah Alvarez, Patrick Fields and Nikki Cheng
Mol Cancer Res February 1 2019 (17) (2) 604-617; DOI: 10.1158/1541-7786.MCR-18-0750
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