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

doi:10.1038/onc.2014.45

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

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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 language	English
Pages (from-to)	4579-4588
Number of pages	10
Journal	Oncogene
Volume	33
Issue number	37
Early online date	24 Mar 2014
DOIs	https://doi.org/10.1038/onc.2014.45
Publication status	Published - 11 Sep 2014

Keywords

Breast cancer
Cancer therapeutic resistance
Tumor immunology

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10.1038/onc.2014.45Licence: CC BY-NC-ND

Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer
This work is licensed under a Creative Commons Attribution- NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/
Final published version, 3.08 MBLicence: CC BY-NC-ND

Valerie Speirs
- School of Medicine, Medical Sciences & Nutrition, Medical Sciences - Chair in Molecular Oncology
- Institute of Medical Sciences
Person: Academic

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title = "Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer",

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. ",

keywords = "Breast cancer, Cancer therapeutic resistance, Tumor immunology",

author = "P-P Wong and Yeoh, {C C} and Ahmad, {A S} and C Chelala and C Gillett and V Speirs and Jones, {J L} and Hurst, {H C}",

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.",

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T1 - Identification of MAGEA antigens as causal players in the development of tamoxifen-resistant breast cancer

AU - Wong, P-P

AU - Yeoh, C C

AU - Ahmad, A S

AU - Chelala, C

AU - Gillett, C

AU - Speirs, V

AU - Jones, J L

AU - Hurst, H C

N1 - 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.

PY - 2014/9/11

Y1 - 2014/9/11

N2 - 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.

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.

KW - Breast cancer

KW - Cancer therapeutic resistance

KW - Tumor immunology

U2 - 10.1038/onc.2014.45

DO - 10.1038/onc.2014.45

M3 - Article

C2 - 24662835

VL - 33

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EP - 4588

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 37

ER -

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

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