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The metastatic potential of triple-negative breast cancer is decreased via caloric restriction-mediated reduction of the miR-17~92 cluster

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Abstract

Caloric restriction (CR) has been shown to cause tumor regression in models of triple-negative breast cancer (TNBC), and the regression is augmented when coupled with ionizing radiation (IR). In this study, we sought to determine if the molecular interaction between CR and IR could be mediated by microRNA (miR). miR arrays revealed 3 miRs in the miR-17~92 cluster as most significantly down regulated when CR is combined with IR. In vivo, CR and IR down regulated miR-17/20 in 2 TNBC models. To elucidate the mechanism by which this cluster regulates the response to CR, cDNA arrays were performed and the top 5 statistically significant gene ontology terms with high fold changes were all associated with extracellular matrix (ECM) and metastases. In silico analysis revealed 4 potential targets of the miR-17~92 cluster related to ECM: collagen 4 alpha 3, laminin alpha 3, and metallopeptidase inhibitors 2 and 3, which were confirmed by luciferase assays. The overexpression or silencing of miR-17/20a demonstrated that those miRs directly affected the ECM proteins. Furthermore, we found that CR-mediated inhibition of miR-17/20a can regulate the expression of ECM proteins. Functionally, we demonstrate that CR decreases the metastatic potential of cells which further demonstrates the importance of the ECM. In conclusion, CR can be used as a potential treatment for cancer because it may alter many molecular targets concurrently and decrease metastatic potential for TNBC.

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Abbreviations

TNBC:

Triple-negative breast cancer

CR:

Caloric restriction

IR:

Radiation

ECM:

Extracellular matrix

miR:

microRNA

COL4A3:

Collagen 4 alpha 3

LAMA3:

Laminin alpha 3

TIMP2 and 3:

Metallopeptidase inhibitors 2 and 3

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Acknowledgments

The study was funded by the NCI Cancer Center Support Grant P30-CA56036 for the Kimmel Cancer Center.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Radiation Oncology, Thomas Jefferson University, Phiadelphia, PA, 19107, USA

    Lianjin Jin, Meng Lim, Yuri Sano, Brittany A. Simone & Nicole L. Simone

  2. Radiation Oncology Branch, National Cancer Institute, NIH, Bethesda, MD, 20892, USA

    Shuping Zhao, Jason E. Savage & Kevin Camphausen

  3. Department of Biochemistry & Molecular Biology, Thomas Jefferson University, Phiadelphia, PA, 19107, USA

    Eric Wickstrom

  4. Department of Cancer Biology, Thomas Jefferson University, Phiadelphia, PA, 19107, USA

    Richard G. Pestell

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  1. Lianjin Jin
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  2. Meng Lim
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Correspondence to Nicole L. Simone.

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Jin, L., Lim, M., Zhao, S. et al. The metastatic potential of triple-negative breast cancer is decreased via caloric restriction-mediated reduction of the miR-17~92 cluster. Breast Cancer Res Treat 146, 41–50 (2014). https://doi.org/10.1007/s10549-014-2978-7

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  • DOI: https://doi.org/10.1007/s10549-014-2978-7

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