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

TitleAndrogen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer.
Publication TypeJournal Article
Year of Publication2015
AuthorsCiupek, A, Rechoum, Y, Gu, G, Gelsomino, L, Beyer, AR, Brusco, L, Covington, KR, Tsimelzon, A, Fuqua, SAW
JournalBreast Cancer Res Treat
Date Published2015 Nov
KeywordsAntineoplastic Agents, Hormonal, Breast Neoplasms, Cell Line, Tumor, Cell Proliferation, Drug Resistance, Neoplasm, Estrogen Receptor alpha, Female, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Signaling System, Protein Binding, Receptor, Epidermal Growth Factor, Receptors, Androgen, rho Guanine Nucleotide Dissociation Inhibitor alpha, Tamoxifen, Transcriptional Activation

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.

Alternate JournalBreast Cancer Res. Treat.
PubMed ID26487496
PubMed Central IDPMC4749407
Grant ListR01 CA072038 / CA / NCI NIH HHS / United States
T32 GM088129 / GM / NIGMS NIH HHS / United States
R01 CA72038 / CA / NCI NIH HHS / United States
T32GM088129 / GM / NIGMS NIH HHS / United States