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Breast Cancer Research and Treatment

, Volume 142, Issue 3, pp 537–548 | Cite as

Tamoxifen selects for breast cancer cells with mammosphere forming capacity and increased growth rate

  • Diego Raffo
  • Damian E. Berardi
  • Osvaldo Pontiggia
  • Laura Todaro
  • Elisa Bal de Kier Joffé
  • Marina SimianEmail author
Preclinical study

Abstract

Using the M05 mouse mammary tumor model and the MCF-7 cell line, we investigated the effect of tamoxifen treatment on the fraction of breast cancer cells with self-renewing capacity both in vitro and in vivo. We found that pretreatment with 4-OH-tamoxifen leads to an increase in cells with the ability of forming mammospheres that express lower levels of ER-α and increased expression of transcription factors associated with pluripotency. Moreover, exposure on plastic to 4-OH-tamoxifen by itself leads to an upregulation of these transcription factors. M05 tumors grown in mice treated with tamoxifen have a higher percentage of cells with self-renewing capacity and this proportion is conserved when tumors are passaged to nontreated mice. Furthermore, interruption of tamoxifen leads to increased tumor growth compared to tumors grown in mice that were never exposed to the antiestrogen. In addition, these tumors are characterized by a higher number of CD24lCD29h cells compared to tumors grown in nontreated mice. Treatment in vitro with 4-OH-tamoxifen for 5 days leads to a long lasting increase in the proportion of cells with self-renewing capacity even after 1 month of growth in the absence of the antiestrogen. Finally, we compared the mammosphere forming capacity of hormone dependent and independent passages of the M05 tumor and found that hormone independence is associated to an increase in cells with self-renewing capacity. Our results support previous findings that suggest that endocrine treatment selects for cells with stem cell properties.

Keywords

Breast cancer Tamoxifen resistance Stem cells Self-renewing capacity Estrogen receptor 

Notes

Acknowledgments

This work is supported by Grants from MINCYT (PICT 2008-0325) and Florencio Fiorini Foundation to MS, Conicet PIP 112 20110100557 grant to LT, and PICT 2010-01296 (MINCYT) and M00243 (UBACyT) to EBKJ.

Conflict of interests

The authors declare they have no competing interests.

Supplementary material

10549_2013_2760_MOESM1_ESM.eps (54 mb)
Fig. S1 Quantification of the changes in levels of transcription factors associated to stemness. a Densitometry of RT-PCR results shown in Fig. 2a corresponding to MCF-7 cells grown on plastic and treated with 4-OH-tamoxifen (2D-4-OH-TAM) or grown as mammospheres. Values are expressed as arbitrary units (A.U.) relative to the levels of GADPH. They are normalized against the bands corresponding to the cells grown on 2D in the absence of 4-OH-Tamoxifen (2D). b The same analysis was carried out for the results obtained with LM05-E cells. (EPS 55300 kb)

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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Diego Raffo
    • 1
  • Damian E. Berardi
    • 1
  • Osvaldo Pontiggia
    • 1
  • Laura Todaro
    • 1
  • Elisa Bal de Kier Joffé
    • 1
  • Marina Simian
    • 1
    Email author
  1. 1.Research Area, Área InvestigaciónInstituto de Oncología “Angel H. Roffo”Buenos AiresArgentina

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