Breast Cancer Research and Treatment

, Volume 154, Issue 2, pp 225–237 | Cite as

Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer

  • Andrew Ciupek
  • Yassine Rechoum
  • Guowei Gu
  • Luca Gelsomino
  • Amanda R. Beyer
  • Lauren Brusco
  • Kyle R. Covington
  • Anna Tsimelzon
  • Suzanne A. W. Fuqua
Preclinical study

Abstract

Tamoxifen (Tam) resistance represents a significant clinical problem in estrogen receptor (ER) α-positive breast cancer. We previously showed that decreased expression of Rho guanine nucleotide dissociation inhibitor (Rho GDI) α, a negative regulator of the Rho GTPase pathway, is associated with Tam resistance. We now discover that androgen receptor (AR) is overexpressed in cells with decreased Rho GDIα and seek to determine AR’s contribution to resistance. We engineered ERα-positive cell lines with stable knockdown (KD) of Rho GDIα (KD cells). Resistance mechanisms were examined using microarray profiling, protein-interaction studies, growth and reporter gene assays, and Western blot analysis combined with a specific AR antagonist and other signaling inhibitors. Tam-resistant tumors and cell lines with low Rho GDIα levels exhibited upregulated AR expression. Microarray of Rho GDIα KD cells indicated that activation of EGFR and ERα was associated with Tam treatment. When AR levels were elevated, interaction between AR and EGFR was detected. Constitutive and Tam-induced phosphorylation of EGFR and ERK1/2 was blocked by the AR antagonist Enzalutamide, suggesting that AR-mediated EGFR activation was a mechanism of resistance in these cells. Constitutive ERα phosphorylation and transcriptional activity was inhibited by Enzalutamide and the EGFR inhibitor gefitinib, demonstrating that AR-mediated EGFR signaling activated ERα. Tam exhibited agonist activity in AR overexpressing cells, stimulating ERα transcriptional activity and proliferation, which was blocked by Enzalutamide and gefitinib. We describe a novel model of AR-mediated Tam resistance through activation of EGFR signaling leading to ER activation in ERα-positive cells with low expression of Rho GDIα.

Keywords

Androgen receptor Epidermal growth factor receptor Estrogen receptor Breast cancer Endocrine therapy resistance Tamoxifen 

Supplementary material

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Andrew Ciupek
    • 1
    • 5
  • Yassine Rechoum
    • 1
  • Guowei Gu
    • 1
  • Luca Gelsomino
    • 2
  • Amanda R. Beyer
    • 1
  • Lauren Brusco
    • 3
  • Kyle R. Covington
    • 4
  • Anna Tsimelzon
    • 1
  • Suzanne A. W. Fuqua
    • 1
  1. 1.Lester and Sue Smith Breast CenterBaylor College of MedicineHoustonUSA
  2. 2.Department of Pharmacy, Health, and Nutritional SciencesUniversity of CalabriaCosenzaItaly
  3. 3.Sheikh Kahlifa Bin Zayed Al Nahyan Institute for Personalized Cancer TherapyUniversity of Texas MD Anderson Cancer CenterHoustonUSA
  4. 4.Human Genome Sequencing CenterBaylor College of MedicineHoustonUSA
  5. 5.Interdepartmental Program in Translational Biology and Molecular MedicineBaylor College of MedicineHoustonUSA

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