Breast Cancer Research and Treatment

, Volume 121, Issue 1, pp 1–11 | Cite as

Androgen receptor overexpression induces tamoxifen resistance in human breast cancer cells

  • Francesca De Amicis
  • Janagi Thirugnansampanthan
  • Yukun Cui
  • Jennifer Selever
  • Amanda Beyer
  • Irma Parra
  • Nancy L. Weigel
  • Matthew H. Herynk
  • Anna Tsimelzon
  • Michael T. Lewis
  • Gary C. Chamness
  • Susan G. Hilsenbeck
  • Sebastiano Andò
  • Suzanne A. W. Fuqua
Preclinical study

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.

Keywords

Androgen receptor Breast cancer Tamoxifen resistance 

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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Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Francesca De Amicis
    • 1
    • 2
  • Janagi Thirugnansampanthan
    • 1
  • Yukun Cui
    • 1
  • Jennifer Selever
    • 1
  • Amanda Beyer
    • 1
  • Irma Parra
    • 1
  • Nancy L. Weigel
    • 3
  • Matthew H. Herynk
    • 1
  • Anna Tsimelzon
    • 1
  • Michael T. Lewis
    • 1
  • Gary C. Chamness
    • 1
  • Susan G. Hilsenbeck
    • 1
  • Sebastiano Andò
    • 4
  • Suzanne A. W. Fuqua
    • 1
  1. 1.Breast Center, Baylor College of MedicineHoustonUSA
  2. 2.Department of Pharmaco-BiologyUniversity of CalabriaCosenzaItaly
  3. 3.Department of Molecular and Cellular BiologyBaylor College of MedicineHoustonUSA
  4. 4.Department of Cellular BiologyUniversity of CalabriaCosenzaItaly

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