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Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

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Abstract

Estrogen receptor-α (ERα) positive breast cancer frequently responds to inhibitors of ERα activity, such as tamoxifen, and/or to aromatase inhibitors that block estrogen biosynthesis. However, many patients become resistant to these agents through mechanisms that remain unclear. Previous studies have shown that expression of ERα in ERα-negative breast cancer cell lines frequently inhibits their growth. In order to determine the consequence of ERα over-expression in ERα-positive breast cancer cells, we over-expressed ERα in the MCF-7 breast cancer cell line using adenovirus gene transduction. ERα over-expression led to ligand-independent expression of the estrogen-regulated genes pS2 and PR and growth in the absence of estrogen. Interestingly, prolonged culturing of these cells in estrogen-free conditions led to the outgrowth of cells capable of growth in cultures from ERα transduced, but not in control cultures. From these cultures a line, MLET5, was established which remained ERα-positive, but grew in an estrogen-independent manner. Moreover, MLET5 cells were inhibited by anti-estrogens showing that ERα remains important for their growth. Gene expression microarray analysis comparing MCF-7 cells with MLET5 highlighted apoptosis as a major functional grouping that is altered in MLET5 cells, such that cell survival would be favoured. This conclusion was further substantiated by the demonstration that MLET5 show resistance to etoposide-induced apoptosis. As the gene expression microarray analysis also shows that the apoptosis gene set differentially expressed in MLET5 is enriched for estrogen-regulated genes, our findings suggest that transient over-expression of ERα could lead to increased cell survival and the development of estrogen-independent growth, thereby contributing to resistance to endocrine therapies in breast cancer patients.

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Acknowledgments

We would like to thank Georges Vassaux and Nick Lemoine for facilitating the generation of the adenoviruses used in this study. This work was made possible by grants from Cancer Research UK and the Breast Cancer Research Trust. We are grateful for support from the NIHR Biomedical Research Centre funding scheme. We also thank the CR-UK and the Dept of Health funded Imperial College Experimental Cancer Medicine Centre (ECMC).

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The authors declare no conflict of interest.

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Authors and Affiliations

  1. Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK

    Robert S. Tolhurst, Ross S. Thomas, Fiona J. Kyle, Hetal Patel, Manikandan Periyasamy, Andrew Photiou, Paul T. R. Thiruchelvam, Chun-Fui Lai, Marwa Al-sabbagh, Rosemary A. Fisher, R. Charles Coombes, Tahereh Kamalati, Simak Ali & Laki Buluwela

  2. Centre for Molecular Oncology & Imaging, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, Institute of Cancer, Charterhouse Square, London, EC1M 6BQ, UK

    Sayka Barry & Tatjana Crnogorac-Jurcevic

  3. Breakthrough Breast Cancer Centre, Institute of Cancer Research, London, SW3 6JJ, UK

    Lesley-Ann Martin & Mitch Dowsett

  4. The Royal Marsden Hospital, London, SW3 6JB, UK

    Mitch Dowsett

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  1. Robert S. Tolhurst
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Correspondence to Simak Ali or Laki Buluwela.

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Robert S. Tolhurst and Ross S. Thomas should be considered as joint first authors.

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Tolhurst, R.S., Thomas, R.S., Kyle, F.J. et al. Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth. Breast Cancer Res Treat 128, 357–368 (2011). https://doi.org/10.1007/s10549-010-1122-6

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  • DOI: https://doi.org/10.1007/s10549-010-1122-6

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