Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer

P-P Wong* (Corresponding Author), C C Yeoh, A S Ahmad, C Chelala, C Gillett, V Speirs, J L Jones, H C Hurst

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)
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Abstract

The antiestrogen tamoxifen is a well-tolerated, effective treatment for estrogen receptor-α-positive (ER+) breast cancer, but development of resistance eventually limits its use. Here we show that expression of MAGEA2, and related members of this cancer-testis antigen family, is upregulated in tamoxifen-resistant tumor cells. Expression of MAGEA2 in tumor lines grown in vitro or as xenografts led to continued proliferation in the presence of tamoxifen. At the molecular level, we demonstrate that MAGEA2 protein localizes to the nucleus and forms complexes with p53 and ERα, resulting in repression of the p53 pathway but increased ER-dependent signaling. In a series of ER+, tamoxifen-treated breast cancer patients, we show a highly significant (P=0.006) association between MAGEA (melanoma-associated antigen) expression and reduced overall survival, confirming the clinical significance of our observations.

Original languageEnglish
Pages (from-to)4579-4588
Number of pages10
JournalOncogene
Volume33
Issue number37
Early online date24 Mar 2014
DOIs
Publication statusPublished - 11 Sept 2014
Externally publishedYes

Bibliographical note

We are grateful to our colleagues Andrew Clear, Keyur Trivedi and Abeer Shaaban for technical assistance with the TMA for the BLT and Leeds cases, respectively, Dr Yaohe Wang for help with scoring the Immunohistochemistry study, Ian Hart and Steven Robinson for invaluable advice and help with the xenograft study and to Richard Grose for useful comments on the manuscript. We thank Tracey Chapman for expert handling of the Affymetrix arrays and Simak Ali, Dennis McCance and Hinrich Gronemeyer for the generous provision of reagents. This work was funded by Cancer Research UK and Barts and the London Charity.

Keywords

  • Breast cancer
  • Cancer therapeutic resistance
  • Tumor immunology

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