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Divergent roles of CXCR3 isoforms in promoting cancer stem-like cell survival and metastasis

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Abstract

There is growing evidence that several chemokine receptors including CXCR3 contribute to metastasis of breast and other cancers, however, in order to target CXCR3 effectively, it is critical to understand the relative contribution of each CXCR3 isoform. Furthermore, the possible contribution of either major CXCR3 isoform (CXCR3-A, CXCR3-B) to cancer stem cell behavior has not been reported. We employed primary invasive ductal carcinomas, a panel of breast cell lines, and a xenograft model of metastatic breast cancer to examine the role of CXCR3 isoforms in the behavior of breast cancer stem-like cells and the contribution of each isoform to metastasis. In primary human breast cancer specimens as well as established breast cancer cell lines, CXCR3-A is more highly expressed than CXCR3-B. Conversely, immortalized normal MCF10A cells express more CXCR3-B relative to CXCR3-A. Overexpression of CXCR3-B in MDA-MB-231 basal-like cells inhibits CXCR3 ligand-stimulated proliferation, which is accompanied by reduced ligand-mediated activation of ERK1/2 and p38 kinases. Likewise, metastatic capacity is reduced in vivo by higher levels of CXCR3-B, and migratory and invasive properties are inhibited in vitro; conversely, silencing of CXCR3-B enhances lung colonization. In contrast to the anti-metastatic and anti-proliferative roles of CXCR3-B in the non-stem cell population, this isoform supports a cancer stem-like cell phenotype. CXCR3-B is markedly elevated in mammosphere-forming parental cells and overexpressing CXCR3-B further enhances mammosphere-forming potential as well as growth in soft agar; stem-like behavior is inhibited in MDA-MB-231shCXCR3-B cells. Targeting of both CXCR3 isoforms may be important to block the stem cell-promoting actions of CXCR3-B, while inhibiting the pro-proliferative and metastasis-promoting functions of CXCR3-A.

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Acknowledgement

We thank Dr. Steven Kelsen, Temple University for the provision of a CXCR3-B retroviral expression plasmid. This study was supported by the U.S. Department of Defense Breast Cancer Research Program.

Conflict of interest

All authors declare no conflict of interest.

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Authors and Affiliations

  1. University of Maryland Greenebaum Cancer Center, 655 W. Baltimore Street, Baltimore, MD, 21201, USA

    Yanchun Li, Jocelyn C. Reader, Xinrong Ma, Namita Kundu, Tyler Kochel & Amy M. Fulton

  2. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Namita Kundu & Amy M. Fulton

  3. Baltimore Veterans Administration, 10 N. Greene Street, Baltimore, MD, 21201, USA

    Amy M. Fulton

Authors
  1. Yanchun Li
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  2. Jocelyn C. Reader
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  3. Xinrong Ma
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  4. Namita Kundu
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  5. Tyler Kochel
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  6. Amy M. Fulton
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Correspondence to Amy M. Fulton.

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Li, Y., Reader, J.C., Ma, X. et al. Divergent roles of CXCR3 isoforms in promoting cancer stem-like cell survival and metastasis. Breast Cancer Res Treat 149, 403–415 (2015). https://doi.org/10.1007/s10549-014-3229-7

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  • DOI: https://doi.org/10.1007/s10549-014-3229-7

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