Abstract
Background
Metastatic triple-negative breast cancer (mTNBC) is treated mainly with chemotherapy. However, resistance frequently occurs as tumours enter dormancy. Statins have been suggested as effective against cancer but as they prolong and promote dormancy, it is an open question of whether the concomitant use would interfere with chemotherapy in primary and mTNBC. We examined this question in animal models and clinical correlations.
Methods
We used a xenograft model of spontaneous metastasis to the liver from an ectopic tumour employing a mTNBC cell line. Atorvastatin was provided to sensitise metastatic cells, followed by chemotherapy. The effects of statin usage on outcomes in women with metastatic breast cancer was assessed respectively by querying a database of those diagnosed from 1999 to 2019.
Results
Atorvastatin had limited influence on tumour growth or chemotherapy effects in ectopic primary tumours. Interestingly, atorvastatin was additive with doxorubicin (but not paclitaxel) when targeting liver metastases. E-cadherin-expressing, dormant, breast cancer cells were resistant to the use of either statins or chemotherapy as compared to wild-type cells; however, the combination of both did lead to increased cell death. Although prospective randomised studies are needed for validation, our retrospective clinical analysis suggested that patients on statin treatment could experience prolonged dormancy and overall survival; still once the tumour recurred progression was not affected by statin use.
Conclusion
Atorvastatin could be used during adjuvant chemotherapy and also in conjunction with metastatic chemotherapy to reduce mTNBC cancer progression. These preclinical data establish a rationale for the development of randomised studies.
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Data availability
Data supporting the conclusions of this manuscript are included within the article and the Supplementary Figures.
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Acknowledgements
The authors thank the other members of the laboratories of Wells and Dr. Partha Roy (University of Pittsburgh) for helpful suggestions and critiques. Dr. Zoltain Oltvai (University of Rochester) is also thanked for his insights into cellular metabolics and statin effects. This project also used the Pitt Biospecimen Core shared resource which is supported in part by award P30CA047904. The members of the Center for Biological Imaging (CBI) at the University of Pittsburgh are also thanked for sharing their services.
Funding information
These studies were made possible by funds from the VA Merit Award Basic Laboratory Sciences Research Program (to AW), a NIH F30 (to CB), and a DoD CDMRP in Breast Cancer (to AMC).
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JLGM, CHB and AW conceived the study, designed, and performed in vivo experiments. JLGM and AW wrote the manuscript. JLGM performed in vitro experiments and experimental and clinical analysis. AMC helped with hepatocyte culture and manuscript edition. All authors read, edited, and approved the final manuscript.
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Animal studies were approved and done in compliance with the Pittsburgh VA Institutional Animal Care and Use Committee (IACUC) and Institutional Biosafety Committee (IBC) under protocol name “Molecular Regulation of Breast Cancer Progression” (ID:03017). Cell lines used are obtained from the American Type Culture Collection. Clinical retrospective studies were IRB-approved (STUDY20030072) by the University of Pittsburgh Human Research Protection Office (HRPO).
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Marti, J.L.G., Beckwitt, C.H., Clark, A.M. et al. Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer. Br J Cancer 125, 1285–1298 (2021). https://doi.org/10.1038/s41416-021-01529-0
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DOI: https://doi.org/10.1038/s41416-021-01529-0
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