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  • Oncogenomics
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Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Oncogene volume 29, pages 6071–6083 (2010)Cite this article

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Abstract

Endocrine therapies targeting the proliferative effect of 17β-estradiol through estrogen receptor α (ERα) are the most effective systemic treatment of ERα-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The long-term estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7–LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERα. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERα transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)- to pS167-ERα were observed during MCF7–LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7–LTED and breast tumor transcriptome profiles that characterize ERα-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7–LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

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Acknowledgements

This study was funded by the Spanish Ministry of Health CIBERESP and grant 06/0545 and the Ministry of Science and Innovation (MICINN) grant SAF06/05399. HA was supported by a MICINN postdoctoral fellowship and MAP was a ‘Ramón y Cajal’ Researcher with the MICINN.

Author information

Authors and Affiliations

  1. Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Institute for Biomedical Research (IDIBELL), L’Hospitalet, Barcelona, Spain

    H Aguilar, A Urruticoechea & M A Pujana

  2. Biomarkers and Susceptibility Unit, Catalan Institute of Oncology, IDIBELL, L’Hospitalet, Barcelona, Spain

    X Solé, N Bonifaci, J Serra-Musach & M A Pujana

  3. Biomedical Research Centre Network for Epidemiology and Public Health, Catalan Institute of Oncology, IDIBELL, L'Hospitalet, Barcelona, Spain

    X Solé, N Bonifaci, J Serra-Musach & M A Pujana

  4. Department of Experimental and Health Science, Research Unit on Biomedical Informatics, Pompeu Fabra University, Barcelona Biomedical Research Park, Barcelona, Spain

    A Islam & N López-Bigas

  5. Epithelial Carcinogenesis Group, Molecular Pathology Programme, Spanish National Cancer Research Centre, Madrid, Spain

    M Méndez-Pertuz

  6. Division of Molecular Carcinogenesis, Center for Biomedical Genetics and Cancer Genomics Center, Netherlands Cancer Institute, Amsterdam, The Netherlands

    R L Beijersbergen

  7. Molecular Diagnostics Unit, Hereditary Cancer Program, Catalan Institute of Oncology, IDIBELL, L’Hospitalet, Barcelona, Spain

    C Lázaro

Authors
  1. H Aguilar
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  2. X Solé
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  3. N Bonifaci
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  4. J Serra-Musach
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  5. A Islam
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  6. N López-Bigas
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  7. M Méndez-Pertuz
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  8. R L Beijersbergen
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  9. C Lázaro
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  10. A Urruticoechea
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  11. M A Pujana
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Corresponding authors

Correspondence to A Urruticoechea or M A Pujana.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on the Oncogene website

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Aguilar, H., Solé, X., Bonifaci, N. et al. Biological reprogramming in acquired resistance to endocrine therapy of breast cancer. Oncogene 29, 6071–6083 (2010). https://doi.org/10.1038/onc.2010.333

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  • DOI: https://doi.org/10.1038/onc.2010.333

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