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Differential characteristics of heart, liver, and brain metastatic subsets of murine breast carcinoma

  • Preclinical Study
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Abstract

Breast carcinoma is comprised of heterogeneous groups of cells with different metastatic potential. To develop effective therapeutic strategies targeting metastatic disease, it is crucial to understand the characteristics of breast cancer cells that enable metastasis to distant organs. 4THM breast carcinoma cells are the cells of 4T1 primary tumors that metastasized to the heart. Cells of 4THM tumors which metastasized to liver (4TLM) were previously isolated. Recently macroscopic brain metastasis in 4THM injected animals, were isolated to obtain a brain metastatic cell line (4TBM). Using an orthotopic mouse model differential characteristic of cells metastasized to heart (4THM), liver (4TLM), and brain (4TBM) were compared for ability to metastasize and expression of stem cell markers. We found that 4TLM cells produced significantly more lung and liver metastasis compared to 4TBM and 4THM cells. In vitro, proliferation as well as migration rate of 4TLM cells was also significantly higher than the other cell lines. Remarkably primary tumors formed by 4TLM cells expressed significant amounts of CD34, a marker for mesenchymal malignancies. Markers of epithelial–mesenchymal transition were expressed in all metastatic cells, but the degree of expression differed. Majorities of 4TLM, 4THM, and 4TBM cells were CD44+ CD24− whereas, 12 % of 4TLM cells also expressed membranous CD24. Conditioned mediums of non-metastatic 67NR breast tumors and cancer-associated fibroblasts inhibited growth of highly metastatic 4TLM cells. Malignant cells metastasized to brain were distinguished by membranous E-cadherin expression that was markedly higher in 4TBM cells grown as spheroids suggesting E-cadherin is required for brain metastasis. Differential features of heart, brain, and liver metastatic cells in a syngenic model was shown in this study for the first time. These findings not only provide a model to explore new treatment modalities, but also demonstrate differential features of cancer cells that originally homed to a certain organ, such as liver or brain.

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Abbreviations

CSC:

Cancer stem cells

EMT:

Epithelial–mesenchymal transition

VEGF:

Vascular endothelial growth factor

SDF 1:

Stromal cell-derived factor-1

CM:

Conditioned mediums

CAF:

Cancer-associated fibroblasts

α-SMA:

α-Smooth muscle actin

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Acknowledgments

Study was supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK Grant No: 109S449). Authors thank Prof. Dr. Necdet Demir for his suggestions in interpreting the immunohistochemical staining, and Sayra Dilmaç for her technical assistance.

Conflict of interest

The authors also declare that they have no competing interests.

Author information

Authors and Affiliations

  1. Department of Medical Pharmacology and SBAUM, School of Medicine, Akdeniz University, Antalya, Turkey

    Nuray Erin, Şule Kale & Özlem Duymuş

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

    Gamze Tanrıöver

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

    Sadi Köksoy

  4. Department of Radiation Oncology, School of Medicine, Akdeniz University, Antalya, Turkey

    Aylin F. Korcum

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  1. Nuray Erin
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  2. Şule Kale
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Correspondence to Nuray Erin.

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Erin, N., Kale, Ş., Tanrıöver, G. et al. Differential characteristics of heart, liver, and brain metastatic subsets of murine breast carcinoma. Breast Cancer Res Treat 139, 677–689 (2013). https://doi.org/10.1007/s10549-013-2584-0

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  • DOI: https://doi.org/10.1007/s10549-013-2584-0

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