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Autocrine control of MIP-2 secretion from metastatic breast cancer cells is mediated by CXCR2: a mechanism for possible resistance to CXCR2 antagonists

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Abstract

CXCR2 interacts with a wide range of chemokines and CXCR2 antagonists may have therapeutic value for treatment-resistant metastatic carcinomas. We aimed to explore regulation of activity of CXCR2 and its ligand, MIP-2, in metastatic breast carcinoma. We used mouse breast carcinoma cells metastasize to brain (4TBM), liver (4TLM), and heart (4THM) and explored the extra- and intracellular mechanisms effecting MIP-2 secretion using CXCR2 antagonist and inhibitors of downstream signaling molecules. 4TBM, 4TLM, and 4THM cells include cancer stem cell features and metastasize extensively. We also determined kinetics of MIP-2 secretion in 4T1 and non-metastatic 67NR mouse breast carcinoma cells. We found that there is an autocrine-inhibition of MIP-2 secretion. Specifically, metastatic cells selectively express CXCR2 only, and not CXCR1 and attenuating CXCR2 activity with SB225002 increased MIP-2 secretion. This may be due to the inhibition of protein kinase C (PKC) activity since RO318220; a specific inhibitor of PKC also increased MIP-2 secretion. Attenuating CXCR2 activity with SB225002, otherwise suppressed proliferation of 4THM and 4TBM cells. Tumor explants and cancer-associated fibroblasts obtained from 4TLM, 4THM, and 4TBM primary tumors secreted high levels of MIP-2. Surprisingly, CXCR2 expression was low in 4TLM cells demonstrating that liver metastatic cells might be resistant to the anti-tumoral effects of CXCR2 antagonists. Our results demonstrated that resistance to anti-proliferative effects of CXCR2 may also arise from feedback increases in MIP-2 secretion. Activation of PI3 K pathway augments MIP-2 secretion, hence possible resistance to the antitumor effects of CXCR2 antagonists might be prevented with inhibitors of PI3 K.

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Abbreviations

CXCR2:

Chemokine (C-X-C motif) receptor 2

IL8 or CXCL8:

Interleukin 8

MIP2:

Macrophage inflammatory protein 2

4THM:

4T1 heart metastasis

4TLM:

4T1 liver metastasis

4TBM:

4T1 brain metastasis

CAF:

Cancer-associated fibroblasts

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Acknowledgments

This study was supported by TUBITAK with 109S449 grant number and by Akdeniz University Research Unit (BAP: 2009.06.0103.006).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Medical Pharmacology, School of Medicine, Akdeniz University, B-blok kat 1 Immunoloji, 07070, Antalya, Turkey

    Nuray Erin & Esra Nizam

  2. Department of Histology and Embryology, School of Medicine, Akdeniz University, Antalya, Turkey

    Gamze Tanrıöver

  3. Department of Medical Microbiology , School of Medicine, Akdeniz University, Antalya, Turkey

    Sadi Köksoy

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  1. Nuray Erin
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  2. Esra Nizam
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Correspondence to Nuray Erin or Esra Nizam.

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Erin, N., Nizam, E., Tanrıöver, G. et al. Autocrine control of MIP-2 secretion from metastatic breast cancer cells is mediated by CXCR2: a mechanism for possible resistance to CXCR2 antagonists. Breast Cancer Res Treat 150, 57–69 (2015). https://doi.org/10.1007/s10549-015-3297-3

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