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The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription

Oncogene volume 22, pages 4973–4982 (2003)Cite this article

Abstract

BAG-1 is a multifunctional protein that interacts with a wide range of cellular targets including heat-shock proteins and some nuclear hormone receptors. BAG-1 exists as three major isoforms, BAG-1L, BAG-1M and BAG-1S. BAG-1L contains a nuclear localization signal, which is not present in the other isoforms, and is predominantly localized in the cell nucleus. Here we have investigated the effects of BAG-1 on function of the oestrogen receptor (ER), a key growth control molecule and target for hormonal therapy in breast cancer. We demonstrate that BAG-1L, but not BAG-1S or BAG-1M, increased oestrogen-dependent transcription in breast cancer cells. BAG-1L interacted with and stimulated the activity of both ER α and β. Although BAG-1L and ERs colocalize to the nucleus, fusing BAG-1S to an heterologous nuclear localization sequence was not sufficient to stimulate transcription. Consistent with an important effect on receptor function, nuclear BAG-1 expression in breast cancers was associated with expression of the progesterone receptor, a transcriptional target of ERα, and was associated with improved survival in patients treated with hormonal therapy. These data suggest that BAG-1L is an important determinant of ER function in vitro and in human breast cancer.

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Acknowledgements

We thank Dr S Ali for kind gifts of reagents. This research was supported by grants from the Association for International Cancer Research, Breast Cancer Campaign and the Cancer Research UK. R Cutress is supported by a Robertson Trust Training Fellowship from the Royal College of Surgeons of Edinburgh, and the 9th Guernsey Research Fellowship from Hope.

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Author notes

  1. Paul A Townsend

    Present address: Medical Molecular Biology Unit, Institute of Child Health, University College London, 30 Guildford Street, London, WC1N 1EH, UK

Authors and Affiliations

  1. Cancer Sciences Division, Cancer Research UK Oncology Unit, School of Medicine, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK

    Ramsey I Cutress, Paul A Townsend, Adam Sharp, Lynn Wood, Matthew Brimmell, Peter WM Johnson & Graham Packham

  2. Department of Pathology, Southampton General Hospital, Tremona Road, Southampton, SO16 6YD, UK

    Anna Maison, Ron Lee & Adrian C Bateman

  3. Medical Statistics, Health Care Research Unit, University of Southampton, Southampton General Hospital, Southampton, SO16 6YD, UK

    Mark A Mullee

  4. Southampton Breast Unit, Royal South Hants Hospital, Brintons Terrace, Southampton, SO14 0YG, UK

    Gavin T Royle

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Correspondence to Graham Packham.

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Cutress, R., Townsend, P., Sharp, A. et al. The nuclear BAG-1 isoform, BAG-1L, enhances oestrogen-dependent transcription. Oncogene 22, 4973–4982 (2003). https://doi.org/10.1038/sj.onc.1206688

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