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

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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.

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Acknowledgements

This work was supported by the National Institutes of Health/National Cancer Institute R01 CA72038, Cancer Prevention and Research Institute of Texas RP120732, and Susan G. Komen for the Cure PG12221410 to SAWF. The project described was supported in part by Award Number T32GM088129 from the National Institute of General Medical Sciences. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.

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Authors and Affiliations

  1. Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Andrew Ciupek, Yassine Rechoum, Guowei Gu, Amanda R. Beyer, Anna Tsimelzon & Suzanne A. W. Fuqua

  2. Department of Pharmacy, Health, and Nutritional Sciences, University of Calabria, Cosenza, Italy

    Luca Gelsomino

  3. Sheikh Kahlifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Lauren Brusco

  4. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    Kyle R. Covington

  5. Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA

    Andrew Ciupek

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  1. Andrew Ciupek
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  2. Yassine Rechoum
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Correspondence to Suzanne A. W. Fuqua.

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Ciupek, A., Rechoum, Y., Gu, G. et al. Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer. Breast Cancer Res Treat 154, 225–237 (2015). https://doi.org/10.1007/s10549-015-3609-7

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