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Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells

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Abstract

Although the androgen receptor (AR) is a known clinical target in prostate cancer, little is known about its possible role in breast cancer. We have investigated the role of AR expression in human breast cancer in response to treatment with the antiestrogen tamoxifen. Resistance to tamoxifen is a major problem in treating women with breast cancer. By gene expression profiling, we found elevated AR and reduced estrogen receptor (ER) α mRNA in tamoxifen-resistant tumors. Exogenous overexpression of AR rendered ERα-positive MCF-7 breast cancer cells resistant to the growth-inhibitory effects of tamoxifen in anchorage-independent growth assays and in xenograft studies in athymic nude mice. AR-overexpressing cells remained sensitive to growth stimulation with dihydrotestosterone. Treatment with the AR antagonist Casodex™ (bicalutamide) reversed this resistance, demonstrating the involvement of AR signaling in tamoxifen resistance. In AR-overexpressing cells, tamoxifen induced transcriptional activation by ERα that could be blocked by Casodex, suggesting that AR overexpression enhances tamoxifen’s agonistic properties. Our data suggest a role for AR overexpression as a novel mechanism of hormone resistance, so that AR may offer a new clinical therapeutic target in human breast cancers.

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Abbreviations

AR:

Androgen receptor

EGF:

Epidermal growth factor

EGFR:

Epidermal growth factor receptor

ERα:

Estrogen receptor alpha

PR:

Progesterone receptor

qRT-PCR:

Quantitative reverse transcriptase-polymerase chain reaction

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Acknowledgments

This work was supported by NIH grants P01-CA30195 and P50-CA58183 (S. A. W. Fuqua), Department of Defense grant DAMD 07-73-220 (J. Thirugnansampanthan), Department of Defense grant DAMD 17-99-01-9399 (Y. Cui), Department of Defense grant DAMD 17-03-0417 (M. Herynk), and NIH T32 CA90221 (J. Selever). S. A. W. Fuqua and N. L. Weigel were also supported by a pilot grant from the Dan L. Duncan Cancer Center at Baylor College of Medicine for this work. We thank Robin Sample for her excellent administrative assistance.

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Authors and Affiliations

  1. Breast Center, Baylor College of Medicine, One Baylor Plaza, BCM 600, Houston, TX, 77030, USA

    Francesca De Amicis, Janagi Thirugnansampanthan, Yukun Cui, Jennifer Selever, Amanda Beyer, Irma Parra, Matthew H. Herynk, Anna Tsimelzon, Michael T. Lewis, Gary C. Chamness, Susan G. Hilsenbeck & Suzanne A. W. Fuqua

  2. Department of Pharmaco-Biology, University of Calabria, Arcavacata di Rende, Cosenza, Italy

    Francesca De Amicis

  3. Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA

    Nancy L. Weigel

  4. Department of Cellular Biology, University of Calabria, Arcavacata di Rende, Cosenza, Italy

    Sebastiano Andò

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  1. Francesca De Amicis
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  2. Janagi Thirugnansampanthan
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  3. Yukun Cui
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  4. Jennifer Selever
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  5. Amanda Beyer
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  7. Nancy L. Weigel
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  10. Michael T. Lewis
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  13. Sebastiano Andò
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  14. Suzanne A. W. Fuqua
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Correspondence to Suzanne A. W. Fuqua.

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The authors F. De Amicis and J. Thirugnansampanthan are co-first authors for this Article.

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De Amicis, F., Thirugnansampanthan, J., Cui, Y. et al. Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells. Breast Cancer Res Treat 121, 1–11 (2010). https://doi.org/10.1007/s10549-009-0436-8

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