Skip to main content

Advertisement

SpringerLink
Log in

Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells

  • Original Article
  • Published:
Breast Cancer Aims and scope Submit manuscript

Abstract

Background

Eribulin mesylate (eribulin), a non-taxane microtubule dynamic inhibitor, has been widely used in the treatment of patients with advanced or metastatic breast cancer. The combined antitumor and anticancer stem cell (CSC) activities of eribulin with endocrine therapeutic agents have not yet been examined in breast cancer cells. We herein investigated the combined effects of eribulin and antiestrogens.

Methods

A panel of eight breast cancer cell lines, including five estrogen receptor (ER)-positive and three ER-negative cell lines, was used. These cells were treated with eribulin and/or the antiestrogen, 4-hydroxytamoxifen or fulvestrant. Their growth inhibitory activities and effects on cell cycle progression, apoptosis, and the CSC population were investigated. CSCs were detected using the CD44/CD24/EpCAM, Aldefluor, and mammosphere assays.

Results

The 50 % growth inhibitory concentrations of eribulin were 0.38–2.64 nM for the eight cell lines tested. Eribulin exhibited significant antitumor activity under estrogen-supplemented conditions in ER-positive breast cancer cells. The combined antitumor activity of eribulin with an antiestrogen was evaluated using the combination index. The combination index was 0.43–1.46 for ER-positive cell lines. The additive antitumor effect of eribulin with 4-OHT was only significant in MCF-7 cells. Eribulin induced the accumulation of G2/M and apoptosis, while antiestrogens induced the retardation of G1–S cell cycle and apoptosis, respectively. Estrogen markedly increased the proportion of CSCs, whereas antiestrogens inhibited increases in ER-positive cell lines. Moreover, eribulin decreased the proportion of CSCs in either ER-positive or ER-negative cell lines. The combined treatment of eribulin with an antiestrogen did not additively decrease the proportion of CSCs in ER-positive cell lines.

Discussion

The results of the present study demonstrated that eribulin had potent antitumor effects on estrogen-stimulated ER-positive breast cancer cells and the combined treatment of eribulin with an antiestrogen resulted in a weakly additive antitumor effect. We herein suggested for the first time that eribulin exhibited anti-CSC effects on either ER-positive or ER-negative breast cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Cortes J, O’Shaughnessy J, Loesch D, Blum JL, Vahdat LT, Petrakova K, et al. EMBRACE (Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389) investigators: Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914–23.

    Article  CAS  PubMed  Google Scholar 

  2. Kaufman PA, Awada A, Twelves C, Yelle L, Perez E, Wanders J, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. 2012 San Antonio Breast Cancer Symposium. Abstract S6-6.

  3. Bezwoda WR, Derman D, De Moor NG, Lange M, Levin J. Treatment of metastatic breast cancer in estrogen receptor positive patients. A randomized trial comparing tamoxifen alone versus tamoxifen plus CMF. Cancer. 1982;50:2747–50.

    Article  CAS  PubMed  Google Scholar 

  4. Viladiu P, Alonso MC, Avella A, Beltrán M, Borrás J, Ojeda B, Bosch FX. Chemotherapy versus chemotherapy plus hormonotherapy in postmenopausal advanced breast cancer patients. A randomized trial. Cancer. 1985;56:2745–50.

    Article  CAS  PubMed  Google Scholar 

  5. Pritchard KI, Paterson AH, Paul NA, Zee B, Fine S, Pater J. Increased thromboembolic complications with concurrent tamoxifen and chemotherapy in a randomized trial of adjuvant therapy for women with breast cancer. National Cancer Institute of Canada Clinical Trials Group Breast Cancer Site Group. J Clin Oncol. 1996;14:2731–7.

    CAS  PubMed  Google Scholar 

  6. Kurebayashi J, Nukatsuka M, Nagase H, Nomura T, Hirono M, Yamamoto Y, et al. Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells. Cancer Chemother Pharmacol. 2007;59:515–25.

    Article  CAS  PubMed  Google Scholar 

  7. Kurebayashi J, Nukatsuka M, Sonoo H, Uchida J, Kiniwa M. Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer. Cancer Chemother Pharmacol. 2010;65:219–25.

    Article  CAS  PubMed  Google Scholar 

  8. Sugimachi K, Maehara Y, Akazawa K, Nomura Y, Eida K, Ogawa M, et al. Postoperative chemo-endocrine treatment with mitomycin C, tamoxifen, and UFT is effective for patients with premenopausal estrogen receptor-positive stage II breast cancer. Nishinihon Cooperative Study Group of Adjuvant Therapy for Breast Cancer. Breast Cancer Res Treat. 1999;56:113–24.

    Article  CAS  PubMed  Google Scholar 

  9. Noguchi S, Koyama H, Uchino J, Abe R, Miura S, Sugimachi K, et al. Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials. J Clin Oncol. 2005;23:2172–84.

    Article  CAS  PubMed  Google Scholar 

  10. Ohashi Y, Watanabe T, Sano M, Koyama H, Inaji H, Suzuki T. Efficacy of oral tegafur–uracil (UFT) as adjuvant therapy as compared with classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in early breast cancer: a pooled analysis of two randomized controlled trials (N.SAS-BC 01 trial and CUBC trial). Breast Cancer Res Treat. 2010;119:633–41.

    Article  CAS  PubMed  Google Scholar 

  11. Liu S, Wicha MS. Targeting breast cancer stem cells. J Clin Oncol. 2010;28:4006–12.

    Article  CAS  PubMed  Google Scholar 

  12. Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF, et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst. 2008;100:672–9.

    Article  CAS  PubMed  Google Scholar 

  13. Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential Paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res. 2009;15:4234–41.

    Article  CAS  PubMed  Google Scholar 

  14. Fillmore CM, Gupta PB, Rudnick JA, Caballero S, Keller PJ, Lander ES, Kuperwasser C. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci USA. 2010;107:21737–2142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Deng H, Zhang XT, Wang ML, Zheng HY, Liu LJ, Wang ZY. ER-α36-mediated rapid estrogen signaling positively regulates ER-positive breast cancer stem/progenitor cells. PLoS One. 2014;9:e88034.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Kurebayashi J, Kurosumi M, Sonoo H. A new human breast cancer cell line, KPL-1 secretes tumour-associated antigens and grows rapidly in female athymic nude mice. Br J Cancer. 1995;71:845–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kurebayashi J, Kurosumi M, Sonoo H. A new human breast cancer cell line, KPL-3C, secretes parathyroid hormone-related protein and produces tumours associated with microcalcifications in nude mice. Br J Cancer. 1996;74:200–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kurebayashi J, Otsuki T, Tang CK, Kurosumi M, Yamamoto S, Tanaka K, et al. Isolation and characterization of a new human breast cancer cell line, KPL-4, expressing the Erb B family receptors and interleukin-6. Br J Cancer. 1999;79:707–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yamashita T, Kurebayashi J, Kanomata N, Shimo T, Moriya T, Sonoo H. Effects of antiestrogens on regulation of cancer stem cell population in breast cancer cells. Breast. 2013;22:S33–4.

    Google Scholar 

  20. Kurebayashi J, Kanomata N, Moriya T, Kozuka Y, Watanabe M, Sonoo H. Preferential antitumor effect of the Src inhibitor dasatinib associated with a decreased proportion of aldehyde dehydrogenase 1-positive cells in breast cancer cells of the basal B subtype. BMC Cancer. 2010;10:568.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Ropero S, Menéndez JA, Vázquez-Martín A, Montero S, Cortés-Funes H, Colomer R. Trastuzumab plus tamoxifen: anti-proliferative and molecular interactions in breast carcinoma. Breast Cancer Res Treat. 2004;86:125–37.

    Article  CAS  PubMed  Google Scholar 

  22. Shimo T, Kurebayashi J, Kanomata N, Yamashita T, Kozuka Y, Moriya T, Sonoo H. Antitumor and anticancer stem cell activity of a poly ADP-ribose polymerase inhibitor olaparib in breast cancer cells. Breast Cancer. 2014;21:75–85.

    Article  PubMed  Google Scholar 

  23. Yoshida T, Ozawa Y, Kimura T, Sato Y, Kuznetsov G, Xu S, et al. Eribulin mesilate suppresses experimental metastasis of breast cancer cells by reversing phenotype from epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) states. Br J Cancer. 2014;110:1497–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Agoulnik SI, Kawano S, Taylor N, Oestreicher J, Matsui J, Chow J, et al. Eribulin mesylate exerts specific gene expression changes in pericytes and shortens pericyte-driven capillary network in vitro. Vasc Cell. 2014;6:3.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Nakshatri H, Srour EF, Badve S. Breast cancerstem cells and intrinsic subtypes: controversies rage on. Curr Stem Cell Res Ther. 2009;4:50–60.

    Article  CAS  PubMed  Google Scholar 

  27. Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P, et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res. 2009;69:1302–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Douville J, Beaulieu R. Balicki D.ALDH1 as a functional marker of cancer stem and progenitor cells. Stem Cells Dev. 2009;18:17–25.

    Article  CAS  PubMed  Google Scholar 

  29. Radisky DC, LaBarge MA. Epithelial–mesenchymal transition and the stem cell phenotype. Cell Stem Cell. 2008;2:511–2.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Esai Co. kindly provided us with eribulin for this study. We thank Dr. Yasumitsu Nishimura and Dr. Takemi Otsuki of the Department of Hygiene, Kawasaki Medical School for their technical advice. We also thank Mrs. Kaoru Tsuboi and Ms. Megumi Ogo for their technical assistance. This work was supported by Research Project Grants from Kawasaki Medical School (25-12 and 26-5) and by Research Grants from Eisai Co. and the Ministry of Education, Culture, Sports, Science, and Technology, Japan (23591911 and 26461964).

Conflict of interest

Junichi Kurebayashi received a research grant from Esai Co. The other authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan

    Junichi Kurebayashi, Tetsumasa Yamashita & Toshiro Shimo

  2. Department of Pathology 2, Kawasaki Medical School, Kurashiki, Okayama, 701-0192, Japan

    Naoki Kanomata & Takuya Moriya

Authors
  1. Junichi Kurebayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoki Kanomata
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Tetsumasa Yamashita
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Toshiro Shimo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takuya Moriya
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Junichi Kurebayashi.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kurebayashi, J., Kanomata, N., Yamashita, T. et al. Antitumor and anticancer stem cell activities of eribulin mesylate and antiestrogens in breast cancer cells. Breast Cancer 23, 425–436 (2016). https://doi.org/10.1007/s12282-014-0580-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12282-014-0580-9

Keywords

Search

Navigation