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

P-P Wong, C C Yeoh, A S Ahmad, C Chelala, C Gillett, V Speirs, J L Jones, H C Hurst

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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 Sep 2014

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Tamoxifen
Breast Neoplasms
Antigens
Melanoma-Specific Antigens
Estrogen Receptor Modulators
Testicular Neoplasms
Heterografts
Estrogen Receptors
Neoplasms
Survival
Proteins
Therapeutics

Cite this

Wong, P-P., Yeoh, C. C., Ahmad, A. S., Chelala, C., Gillett, C., Speirs, V., ... Hurst, H. C. (2014). Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer. Oncogene, 33(37), 4579-4588. https://doi.org/10.1038/onc.2014.45

Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer. / Wong, P-P; Yeoh, C C; Ahmad, A S; Chelala, C; Gillett, C; Speirs, V; Jones, J L; Hurst, H C.

In: Oncogene, Vol. 33, No. 37, 11.09.2014, p. 4579-4588.

Research output: Contribution to journalArticle

Wong, P-P, Yeoh, CC, Ahmad, AS, Chelala, C, Gillett, C, Speirs, V, Jones, JL & Hurst, HC 2014, 'Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer', Oncogene, vol. 33, no. 37, pp. 4579-4588. https://doi.org/10.1038/onc.2014.45
Wong, P-P ; Yeoh, C C ; Ahmad, A S ; Chelala, C ; Gillett, C ; Speirs, V ; Jones, J L ; Hurst, H C. / Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer. In: Oncogene. 2014 ; Vol. 33, No. 37. pp. 4579-4588.
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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.",
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AB - 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.

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