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Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment

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Abstract

Breast cancer can reoccur, often as bone metastasis, many years if not decades after the primary tumor has been treated. The factors that stimulate dormant metastases to grow are not known, but bone metastases are often associated with skeletal trauma. We used a dormancy model of MDA-MB-231BRMS1, a metastasis-suppressed human breast cancer cell line, co-cultured with MC3T3-E1 osteoblasts in a long term, three dimensional culture system to test the hypothesis that bone remodeling cytokines could stimulate dormant cells to grow. The cancer cells attached to the matrix produced by MC3T3-E1 osteoblasts but grew slowly or not at all until the addition of bone remodeling cytokines, TNFα and IL-β. Stimulation of cell proliferation by these cytokines was suppressed with indomethacin, an inhibitor of cyclooxygenase and of prostaglandin production, or a prostaglandin E2 (PGE2) receptor antagonist. Addition of PGE2 directly to the cultures also stimulated cell proliferation. MCF-7, non-metastatic breast cancer cells, remained dormant when co-cultured with normal human osteoblast and fibroblast growth factor. Similar to the MDA-MB-231BRMS1 cells, MCF-7 proliferation increased in response to TNFα and IL-β. These findings suggest that changes in the bone microenvironment due to inflammatory cytokines associated with bone repair or excess turnover may trigger the occurrence of latent bone metastasis.

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Acknowledgments

This work was supported by a pilot grant from METAvivor and by the U.S. Army Medical and Materiel Command Breast Cancer Idea Program, Grant W81WH-1s2-1-0127. We thank Dr. K. Sandeep Prabhu for thoughtful discussion.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, The Pennsylvania State University, 428 S. Frear Laboratory, University Park, PA, 16802, USA

    Donna M. Sosnoski, Robert J. Norgard, Cassidy D. Grove, Shelby J. Foster & Andrea M. Mastro

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  1. Donna M. Sosnoski
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  2. Robert J. Norgard
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  3. Cassidy D. Grove
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  4. Shelby J. Foster
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  5. Andrea M. Mastro
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Correspondence to Andrea M. Mastro.

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Sosnoski, D.M., Norgard, R.J., Grove, C.D. et al. Dormancy and growth of metastatic breast cancer cells in a bone-like microenvironment. Clin Exp Metastasis 32, 335–344 (2015). https://doi.org/10.1007/s10585-015-9710-9

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  • DOI: https://doi.org/10.1007/s10585-015-9710-9

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