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Cellular and Molecular Biology

Atorvastatin facilitates chemotherapy effects in metastatic triple-negative breast cancer

British Journal of Cancer volume 125, pages 1285–1298 (2021)Cite this article

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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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Fig. 1: Efficacy of chemotherapy on ectopic primary tumours of a spleen-to-liver model is not affected by the use of atorvastatin.
Fig. 2: Efficacy of chemotherapy on metastases in the liver is enhanced in the presence of atorvastatin.
Fig. 3: Statin sensitisation correlates with inhibition of Akt phosphorylation.
Fig. 4: Breast cancer cell sensitisation with atorvastatin enhances antiproliferative effects of chemotherapy in vitro.
Fig. 5: Atorvastatin enhances partial mesenchymal-to-epithelial reverting transition (MErT).
Fig. 6: Use of lipophilic statins is associated to prolonged dormancy and overall survival in a retrospective real-world analysis.

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Data availability

Data supporting the conclusions of this manuscript are included within the article and the Supplementary Figures.

References

  1. Dent R, Hanna WM, Trudeau M, Rawlinson E, Sun P, Narod SA. Pattern of metastatic spread in triple-negative breast cancer. Breast Cancer Res Treat. 2009;115:423–8.

    Article  PubMed  Google Scholar 

  2. Telli ML, Gradishar WJ, Ward JH. NCCN guidelines updates: breast cancer. J Natl Compr Canc Netw. 2019;17:552–5.

    PubMed  Google Scholar 

  3. Naumov GN, Townson JL, MacDonald IC, Wilson SM, Bramwell VH, Groom AC, et al. Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Res Treat. 2003;82:199–206.

    Article  CAS  PubMed  Google Scholar 

  4. Desai P, Chlebowski R, Cauley JA, Manson JE, Wu C, Martin LW, et al. Prospective analysis of association between statin use and breast cancer risk in the women’s health initiative. Cancer Epidemiol Biomark Prev. 2013;22:1868–76.

    Article  CAS  Google Scholar 

  5. Desai P, Lehman A, Chlebowski RT, Kwan ML, Arun M, Manson JE, et al. Statins and breast cancer stage and mortality in the Women’s Health Initiative. Cancer Causes Control. 2015;26:529–39.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Goldvaser H, Rizel S, Hendler D, Neiman V, Shepshelovich D, Shochat T, et al. The association between treatment for metabolic disorders and breast cancer characteristics. Int J Endocrinol. 2016;2016:4658469.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Koohestanimobarhan S, Salami S, Imeni V, Mohammadi Z, Bayat O. Lipophilic statins antagonistically alter the major epithelial-to-mesenchymal transition signaling pathways in breast cancer stem-like cells via inhibition of the mevalonate pathway. J Cell Biochem. 2018;120:2515–31.

  8. Langballe R, Cronin-Fenton D, Dehlendorff C, Jensen MB, Ejlertsen B, Andersson M, et al. Statin use and risk of contralateral breast cancer: a nationwide cohort study. Br J Cancer. 2018;119:1297–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Van Wyhe RD, Rahal OM, Woodward WA. Effect of statins on breast cancer recurrence and mortality: a review. Breast Cancer (Dove Med Press). 2017;9:559–65.

    PubMed  PubMed Central  Google Scholar 

  10. Schachter M. Chemical, pharmacokinetic and pharmacodynamic properties of statins: an update. Fundam Clin Pharmacol. 2005;19:117–25.

    Article  CAS  PubMed  Google Scholar 

  11. Stancu C, Sima A. Statins: mechanism of action and effects. J Cell Mol Med. 2001;5:378–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Warita K, Warita T, Beckwitt CH, Schurdak ME, Vazquez A, Wells A, et al. Statin-induced mevalonate pathway inhibition attenuates the growth of mesenchymal-like cancer cells that lack functional E-cadherin mediated cell cohesion. Sci Rep. 2014;4:7593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Beckwitt CH, Brufsky A, Oltvai ZN, Wells A. Statin drugs to reduce breast cancer recurrence and mortality. Breast Cancer Res. 2018;20:144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Yu R, Longo J, van Leeuwen JE, Mullen PJ, Ba-Alawi W, Haibe-Kains B, et al. Statin-induced cancer cell death can be mechanistically uncoupled from prenylation of RAS family proteins. Cancer Res. 2018;78:1347–57.

    Article  CAS  PubMed  Google Scholar 

  15. Beckwitt CH, Shiraha K, Wells A. Lipophilic statins limit cancer cell growth and survival, via involvement of Akt signaling. PLoS ONE 2018;13:e0197422.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. Chao YL, Shepard CR, Wells A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer. 2010;9:179.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Beckwitt CH, Clark AM, Ma B, Whaley D, Oltvai ZN, Wells A. Statins attenuate outgrowth of breast cancer metastases. Br J Cancer. 2018;119:1094–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Amadori D, Volpi A, Maltoni R, Nanni O, Amaducci L, Amadori A, et al. Cell proliferation as a predictor of response to chemotherapy in metastatic breast cancer: a prospective study. Breast Cancer Res Treat. 1997;43:7–14.

    Article  CAS  PubMed  Google Scholar 

  19. Andrzejewski S, Klimcakova E, Johnson RM, Tabaries S, Annis MG, McGuirk S, et al. PGC-1alpha promotes breast cancer metastasis and confers bioenergetic flexibility against metabolic drugs. Cell Metab. 2017;26:778–87 e5.

    Article  CAS  PubMed  Google Scholar 

  20. Ma B, Wheeler SE, Clark AM, Whaley DL, Yang M, Wells A. Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling. Hepatology. 2016;64:1725–42.

    Article  CAS  PubMed  Google Scholar 

  21. Soares KC, Foley K, Olino K, Leubner A, Mayo SC, Jain A, et al. A preclinical murine model of hepatic metastases. J Vis Exp. 2014:51677.

  22. Yoshimura K, Laird LS, Chia CY, Meckel KF, Slansky JE, Thompson JM, et al. Live attenuated Listeria monocytogenes effectively treats hepatic colorectal cancer metastases and is strongly enhanced by depletion of regulatory T cells. Cancer Res. 2007;67:10058–66.

    Article  CAS  PubMed  Google Scholar 

  23. Zenitani M, Nojiri T, Hosoda H, Kimura T, Uehara S, Miyazato M, et al. Chemotherapy can promote liver metastasis by enhancing metastatic niche formation in mice. J Surg Res. 2018;224:50–7.

    Article  CAS  PubMed  Google Scholar 

  24. Palmer G, Chobaz V, Talabot-Ayer D, Taylor S, So A, Gabay C, et al. Assessment of the efficacy of different statins in murine collagen-induced arthritis. Arthritis Rheum. 2004;50:4051–9.

    Article  CAS  PubMed  Google Scholar 

  25. Manu KA, Shanmugam MK, Li F, Chen L, Siveen KS, Ahn KS, et al. Simvastatin sensitizes human gastric cancer xenograft in nude mice to capecitabine by suppressing nuclear factor-kappa B-regulated gene products. J Mol Med (Berl). 2014;92:267–76.

    Article  CAS  PubMed  Google Scholar 

  26. Kato S, Liberona MF, Cerda-Infante J, Sanchez M, Henriquez J, Bizama C, et al. Simvastatin interferes with cancer ‘stem-cell’ plasticity reducing metastasis in ovarian cancer. Endocr Relat Cancer. 2018;25:821–36.

    Article  CAS  PubMed  Google Scholar 

  27. Ottewell PD, Monkkonen H, Jones M, Lefley DV, Coleman RE, Holen I. Antitumor effects of doxorubicin followed by zoledronic acid in a mouse model of breast cancer. J Natl Cancer Inst. 2008;100:1167–78.

    Article  CAS  PubMed  Google Scholar 

  28. Fu Q, Hargrove D, Lu X. Improving paclitaxel pharmacokinetics by using tumor-specific mesoporous silica nanoparticles with intraperitoneal delivery. Nanomedicine. 2016;12:1951–9.

    Article  CAS  PubMed  Google Scholar 

  29. Llesuy SF, Arnaiz SL. Hepatotoxicity of mitoxantrone and doxorubicin. Toxicology. 1990;63:187–98.

    Article  CAS  PubMed  Google Scholar 

  30. Henninger C, Huelsenbeck J, Huelsenbeck S, Grosch S, Schad A, Lackner KJ, et al. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity. Toxicol Appl Pharmacol. 2012;261:66–73.

    Article  CAS  PubMed  Google Scholar 

  31. Li J, Liu J, Liang Z, He F, Yang L, Li P, et al. Simvastatin and Atorvastatin inhibit DNA replication licensing factor MCM7 and effectively suppress RB-deficient tumors growth. Cell Death Dis. 2017;8:e2673.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Henley D, Isbill M, Fernando R, Foster JS, Wimalasena J. Paclitaxel induced apoptosis in breast cancer cells requires cell cycle transit but not Cdc2 activity. Cancer Chemother Pharmacol. 2007;59:235–49.

    Article  CAS  PubMed  Google Scholar 

  33. Kietzmann T. Metabolic zonation of the liver: the oxygen gradient revisited. Redox Biol 2017;11:622–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yu JS, Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016;143:3050–60.

    Article  CAS  PubMed  Google Scholar 

  35. Wolfe AR, Debeb BG, Lacerda L, Larson R, Bambhroliya A, Huang X, et al. Simvastatin prevents triple-negative breast cancer metastasis in pre-clinical models through regulation of FOXO3a. Breast Cancer Res Treat. 2015;154:495–508.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Park YH, Jung HH, Ahn JS, Im YH. Statin induces inhibition of triple negative breast cancer (TNBC) cells via PI3K pathway. Biochem Biophys Res Commun. 2013;439:275–9.

    Article  CAS  PubMed  Google Scholar 

  37. Werfel TA, Elion DL, Rahman B, Hicks DJ, Sanchez V, Gonzales-Ericsson PI, et al. Treatment-induced tumor cell apoptosis and secondary necrosis drive tumor progression in the residual tumor microenvironment through MerTK and IDO1. Cancer Res. 2019;79:171–82.

    Article  CAS  PubMed  Google Scholar 

  38. Robinson DR, Wu YM, Lonigro RJ, Vats P, Cobain E, Everett J, et al. Integrative clinical genomics of metastatic cancer. Nature. 2017;548:297–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Bjarnadottir O, Romero Q, Bendahl PO, Jirstrom K, Ryden L, Loman N, et al. Targeting HMG-CoA reductase with statins in a window-of-opportunity breast cancer trial. Breast Cancer Res Treat. 2013;138:499–508.

    Article  CAS  PubMed  Google Scholar 

  40. Kocaturk B, Versteeg HH. Orthotopic injection of breast cancer cells into the mammary fat pad of mice to study tumor growth. J Vis Exp. 2015;51967.

  41. Henslee AB, Steele TA. Combination statin and chemotherapy inhibits proliferation and cytotoxicity of an aggressive natural killer cell leukemia. Biomark Res. 2018;6:26.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Zhu L, Narloch JL, Onkar S, Joy M, Broadwater G, Luedke C, et al. Metastatic breast cancers have reduced immune cell recruitment but harbor increased macrophages relative to their matched primary tumors. J Immunother Cancer. 2019;7:265.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Miedel MT, Gavlock DC, Jia S, Gough A, Taylor DL, Stern AM. Modeling the effect of the metastatic microenvironment on phenotypes conferred by estrogen receptor mutations using a human liver microphysiological system. Sci Rep. 2019;9:8341.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Weaver BA. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25:2677–81.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Gunasinghe NP, Wells A, Thompson EW, Hugo HJ. Mesenchymal-epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer. Cancer Metastasis Rev. 2012;31:469–78.

    Article  CAS  PubMed  Google Scholar 

  46. Wells A, Yates C, Shepard CR. E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clin Exp Metastasis. 2008;25:621–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Nielsen SF, Nordestgaard BG, Bojesen SE. Statin use and reduced cancer-related mortality. N. Engl J Med. 2012;367:1792–802.

    Article  CAS  PubMed  Google Scholar 

  48. Chae YK, Valsecchi ME, Kim J, Bianchi AL, Khemasuwan D, Desai A, et al. Reduced risk of breast cancer recurrence in patients using ACE inhibitors, ARBs, and/or statins. Cancer Invest. 2011;29:585–93.

    Article  CAS  PubMed  Google Scholar 

  49. Murtola TJ, Visvanathan K, Artama M, Vainio H, Pukkala E. Statin use and breast cancer survival: a nationwide cohort study from Finland. PLoS ONE 2014;9:e110231.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Banys-Paluchowski M, Reinhardt F, Fehm T. Disseminated tumor cells and dormancy in breast cancer progression. Adv Exp Med Biol. 2020;1220:35–43.

    Article  CAS  PubMed  Google Scholar 

  51. Wells A, Griffith L, Wells JZ, Taylor DP. The dormancy dilemma: quiescence versus balanced proliferation. Cancer Res. 2013;73:3811–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Jakobisiak M, Golab J. Statins can modulate effectiveness of antitumor therapeutic modalities. Med Res Rev. 2010;30:102–35.

    Article  CAS  PubMed  Google Scholar 

  53. Calabro A, Tai J, Allen SL, Budman DR. In-vitro synergism of m-TOR inhibitors, statins, and classical chemotherapy: potential implications in acute leukemia. Anticancer Drugs. 2008;19:705–12.

    Article  CAS  PubMed  Google Scholar 

  54. Foulkes WD, Smith IE, Reis-Filho JS. Triple-negative breast cancer. N. Engl J Med. 2010;363:1938–48.

    Article  CAS  PubMed  Google Scholar 

  55. Moon B, Yang SJ, Park SM, Lee SH, Song KS, Jeong EJ, et al. LAD1 expression is associated with the metastatic potential of colorectal cancer cells. BMC Cancer. 2020;20:1180.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Yoon H, Tang CM, Banerjee S, Delgado AL, Yebra M, Davis J, et al. TGF-beta1-mediated transition of resident fibroblasts to cancer-associated fibroblasts promotes cancer metastasis in gastrointestinal stromal tumor. Oncogenesis. 2021;10:13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tatrai E, Bartal A, Gacs A, Paku S, Kenessey I, Garay T, et al. Cell type-dependent HIF1 alpha-mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells. Oncotarget. 2017;8:44498–510.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chang TI, Kang HY, Kim KS, Lee SH, Nam BY, Paeng J, et al. The effect of statin on epithelial-mesenchymal transition in peritoneal mesothelial cells. PLoS ONE. 2014;9:e109628.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Smith C, Alim S, Kadi A, Al Lawati R, Miles M, Hiscox S. Statins suppress the aggressive phenotype of triple negative breast cancer cells via modulation of EGFR signalling. Cancer Res. 2020; https://doi.org/10.1158/1538-7445.SABCS19-P3-11-17.

  60. Padmanaban V, Krol I, Suhail Y, Szczerba BM, Aceto N, Bader JS, et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019;573:439–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kwan ML, Habel LA, Flick ED, Quesenberry CP, Caan B. Post-diagnosis statin use and breast cancer recurrence in a prospective cohort study of early stage breast cancer survivors. Breast Cancer Res Treat. 2008;109:573–9.

    Article  CAS  PubMed  Google Scholar 

  62. Varga D, Koenig J, Kuhr K, Strunz K, Geyer V, Kurzeder C, et al. Comparison of early onset breast cancer patients to older premenopausal breast cancer patients. Arch Gynecol Obstet. 2010;282:427–32.

    Article  PubMed  Google Scholar 

  63. Borgquist S, Ekholm M, Feldt M, Schyman T, Zackrisson S, Bosch A. Abstract OT3-06-03: ABC-SE, Advanced Breast Cancer— Statins and Endocrine treatment. Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5–9; San Antonio, TX Philadelphia (PA): AACR. Cancer Res. 2018;78(4 Suppl):Abstract nr OT3-06-03. 2018.

  64. Torri V, Zambelli A. Multicenter, Randomized, Phase II Study of Neoadjuvant Chemotherapy Associated or Not With Zoledronate and Atorvastatin in Triple Negative Breast Cancers—YAPPETIZER Study 2018. Available from: https://clinicaltrials.gov/ct2/show/NCT03358017.

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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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Authors and Affiliations

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

    Juan Luis Gomez Marti, Colin H. Beckwitt, Amanda M. Clark & Alan Wells

  2. R & D Service, Pittsburgh VA Health System, Pittsburgh, PA, USA

    Juan Luis Gomez Marti, Colin H. Beckwitt, Amanda M. Clark & Alan Wells

  3. UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

    Amanda M. Clark & Alan Wells

  4. Department of Computational & Systems Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Alan Wells

  5. Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA, USA

    Alan Wells

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  1. Juan Luis Gomez Marti
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Contributions

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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Correspondence to Alan Wells.

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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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