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The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers

Oncogene volume 29, pages 4838–4847 (2010)Cite this article

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Abstract

Transcriptomic screens in breast cancer cell lines have identified a protein named anterior gradient-2 (AGR2) as a potentially novel oncogene overexpressed in estrogen receptor (ER) positive tumours. As targeting the ER is responsible for major improvements in cure rates and prevention of breast cancers, we have evaluated the pro-oncogenic function of AGR2 in anti-hormone therapeutic responses. We show that AGR2 expression promotes cancer cell survival in clonogenic assays and increases cell proliferation and viability in a range of cancer cell lines. Chromatin immunoprecipitation and reporter assays indicate that AGR2 is transcriptionally activated by estrogen through ERα. However, we also found that AGR2 expression is elevated rather than inhibited in response to tamoxifen, thus identifying a novel mechanism to account for an agonistic effect of the drug on a specific pro-oncogenic pathway. Consistent with these data, clinical analysis indicates that AGR2 expression is related to treatment failure in ERα-positive breast cancers treated with tamoxifen. In contrast, AGR2 is one of the most highly suppressed genes in cancers of responding patients treated with the anti-hormonal drug letrozole. These data indicate that the AGR2 pathway represents a novel pro-oncogenic pathway for evaluation as anti-cancer drug developments, especially therapies that by-pass the agonist effects of tamoxifen.

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Acknowledgements

We thank Tamara Smerdova and Sona Babcanova for their excellent technical assistance and Larry Hayward for critical discussions. This work was supported by the GACR P301/10/1615, IGA MZ CR NS/9812-4 and MZ0MOU2005. Ted Hupp was supported by grants C483/A10706 and C483/A6354 from the Cancer Research UK, a Breast Cancer Campaign Garfield Weston PhD studentship on AGR2 pathway regulation (AF), and the BBSRC (EM). Mike Dixon was supported by Breakthrough Breast Cancer.

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Authors and Affiliations

  1. Department of Oncological and Experimental Pathology, Masaryk Memorial Cancer Institute, Brno, Czech Republic

    R Hrstka, R Nenutil, K Petrakova, P Muller & B Vojtesek

  2. University of Edinburgh, Institute of Genetics and Molecular Medicine and Cancer Research UK p53 Signal Transduction Laboratories, Edinburgh, UK

    A Fourtouna, M M Maslon, C Naughton, S Langdon, E Murray & T R Hupp

  3. The Edinburgh Breast Unit, Western General Hospital, Edinburgh, UK

    A Larionov & M J Dixon

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  1. R Hrstka
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Correspondence to B Vojtesek.

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Hrstka, R., Nenutil, R., Fourtouna, A. et al. The pro-metastatic protein anterior gradient-2 predicts poor prognosis in tamoxifen-treated breast cancers. Oncogene 29, 4838–4847 (2010). https://doi.org/10.1038/onc.2010.228

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