Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer.
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.
Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.|Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA.
Andrew
A
Ciupek
Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Yassine
Y
Rechoum
Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Guowei
G
Gu
Department of Pharmacy, Health, and Nutritional Sciences, University of Calabria, Cosenza, Italy.
Luca
L
Gelsomino
Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Amanda R
AR
Beyer
Sheikh Kahlifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Lauren
L
Brusco
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Kyle R
KR
Covington
Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
Anna
A
Tsimelzon
Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. sfuqua@bcm.edu.
Suzanne A W
SA
Fuqua
D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D011485:Protein Binding; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D015533:Transcriptional Activation; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha / Q000378:metabolism
D018931:Antineoplastic Agents, Hormonal; D047628:Estrogen Receptor alpha; D011944:Receptors, Androgen; D062948:rho Guanine Nucleotide Dissociation Inhibitor alpha; D013629:Tamoxifen; D066246:ErbB Receptors
Androgen receptor; Breast cancer; Endocrine therapy resistance; Epidermal growth factor receptor; Estrogen receptor; Tamoxifen