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Translational Therapeutics

Statins attenuate outgrowth of breast cancer metastases

British Journal of Cancervolume 119pages10941105 (2018) | Download Citation

Subjects

Abstract

Background

Metastasis in breast cancer foreshadows mortality, as clinically evident disease is aggressive and generally chemoresistant. Disseminated breast cancer cells often enter a period of dormancy for years to decades before they emerge as detectable cancers. Harboring of these dormant cells is not individually predictable, and available information suggests that these micrometastatic foci cannot be effectively targeted by existing therapies. As such, long-term, relatively non-toxic interventions that prevent metastatic outgrowth would be an advance in treatment. Epidemiological studies have found that statins reduce breast cancer specific mortality but not the incidence of primary cancer. However, the means by which statins reduce mortality without affecting primary tumor development remains unclear.

Methods

We examine statin efficacy against two breast cancer cell lines in models of breast cancer metastasis: a 2D in vitro co-culture model of breast cancer cell interaction with the liver, a 3D ex vivo microphysiological system model of breast cancer metastasis, and two independent mouse models of spontaneous breast cancer metastasis to the lung and liver, respectively.

Results

We demonstrate that statins can directly affect the proliferation of breast cancer cells, specifically at the metastatic site. In a 2D co-culture model of breast cancer cell interaction with the liver, we demonstrate that atorvastatin can directly suppress proliferation of mesenchymal but not epithelial breast cancer cells. Further, in an ex vivo 3D liver microphysiological system of breast cancer metastasis, we found that atorvastatin can block stimulated emergence of dormant breast cancer cells. In two independent models of spontaneous breast cancer metastasis to the liver and to the lung, we find that statins significantly reduce proliferation of the metastatic but not primary tumor cells.

Conclusions

As statins can block metastatic tumor outgrowth, they should be considered for use as long-term adjuvant drugs to delay clinical emergence and decrease mortality in breast cancer patients.

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Acknowledgements

We thank the members of the Wells laboratory for discussions and technical assistance. Additionally, we thank the VA Pittsburgh Healthcare System Animal Facility staff for maintaining our mice.

Authors’ contributions

C.H.B., A.M.C., B.M., Z.N.O., and A.W. designed the experiments, C.H.B., B.M., D.W., and A.M.C. conducted the experiments, C.H.B. and A.W. analyzed the data, C.H.B. drafted the manuscript, and all authors have written and edited the manuscript and approved the final version.

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Affiliations

  1. Department of Pathology, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    • Colin H. Beckwitt
    • , Amanda M. Clark
    • , Bo Ma
    • , Zoltán N. Oltvai
    •  & Alan Wells
  2. University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    • Colin H. Beckwitt
    •  & Alan Wells
  3. Pittsburgh VA Health System, Pittsburgh, PA, 15213, USA

    • Colin H. Beckwitt
    • , Bo Ma
    • , Diana Whaley
    •  & Alan Wells
  4. Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    • Zoltán N. Oltvai
    •  & Alan Wells
  5. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    • Alan Wells

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Conflict of interest

The authors declare that they have no conflict of interest.

Availability of data and materials

All data not included in this manuscript or the supplementary materials will be available upon request.

Ethics approval and consent to participate

Use of human cells were adjudicated as exempted by the University of Pittsburgh IRB, and all animal investigations were approved by the Pittsburgh VA Health System IACUC.

Funding

This work was supported by a VA Merit Award (AW) and NIH grants (TR000496 – AW, and CA199947 – CHB).

Note

This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International licence (CC BY 4.0).

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Correspondence to Alan Wells.

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DOI

https://doi.org/10.1038/s41416-018-0267-7