PMID- 26487496 OWN - NLM STAT- MEDLINE DCOM- 20160909 LR - 20210429 IS - 1573-7217 (Electronic) IS - 0167-6806 (Print) IS - 0167-6806 (Linking) VI - 154 IP - 2 DP - 2015 Nov TI - Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERalpha-positive breast cancer. PG - 225-37 LID - 10.1007/s10549-015-3609-7 [doi] AB - Tamoxifen (Tam) resistance represents a significant clinical problem in estrogen receptor (ER) alpha-positive breast cancer. We previously showed that decreased expression of Rho guanine nucleotide dissociation inhibitor (Rho GDI) alpha, 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 GDIalpha and seek to determine AR's contribution to resistance. We engineered ERalpha-positive cell lines with stable knockdown (KD) of Rho GDIalpha (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 GDIalpha levels exhibited upregulated AR expression. Microarray of Rho GDIalpha KD cells indicated that activation of EGFR and ERalpha 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 ERalpha phosphorylation and transcriptional activity was inhibited by Enzalutamide and the EGFR inhibitor gefitinib, demonstrating that AR-mediated EGFR signaling activated ERalpha. Tam exhibited agonist activity in AR overexpressing cells, stimulating ERalpha 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 ERalpha-positive cells with low expression of Rho GDIalpha. FAU - Ciupek, Andrew AU - Ciupek A AD - Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. AD - Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, TX, USA. FAU - Rechoum, Yassine AU - Rechoum Y AD - Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. FAU - Gu, Guowei AU - Gu G AD - Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. FAU - Gelsomino, Luca AU - Gelsomino L AD - Department of Pharmacy, Health, and Nutritional Sciences, University of Calabria, Cosenza, Italy. FAU - Beyer, Amanda R AU - Beyer AR AD - Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. FAU - Brusco, Lauren AU - Brusco L AD - Sheikh Kahlifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA. FAU - Covington, Kyle R AU - Covington KR AD - Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA. FAU - Tsimelzon, Anna AU - Tsimelzon A AD - Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. FAU - Fuqua, Suzanne A W AU - Fuqua SA AD - Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. sfuqua@bcm.edu. LA - eng GR - T32GM088129/GM/NIGMS NIH HHS/United States GR - P50 CA058183/CA/NCI NIH HHS/United States GR - R01 CA072038/CA/NCI NIH HHS/United States GR - T32 GM088129/GM/NIGMS NIH HHS/United States GR - R01 CA72038/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20151020 PL - Netherlands TA - Breast Cancer Res Treat JT - Breast cancer research and treatment JID - 8111104 RN - 0 (Antineoplastic Agents, Hormonal) RN - 0 (Estrogen Receptor alpha) RN - 0 (Receptors, Androgen) RN - 0 (rho Guanine Nucleotide Dissociation Inhibitor alpha) RN - 094ZI81Y45 (Tamoxifen) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM MH - Antineoplastic Agents, Hormonal/pharmacology/therapeutic use MH - Breast Neoplasms/*genetics/*metabolism/pathology MH - Cell Line, Tumor MH - Cell Proliferation MH - Drug Resistance, Neoplasm MH - ErbB Receptors/*genetics/metabolism MH - Estrogen Receptor alpha/*agonists/*metabolism MH - Female MH - Gene Expression MH - Gene Expression Profiling MH - Gene Expression Regulation, Neoplastic/*drug effects MH - Humans MH - MAP Kinase Signaling System/drug effects MH - Protein Binding MH - Receptors, Androgen/genetics/*metabolism MH - Tamoxifen/*pharmacology/therapeutic use MH - Transcriptional Activation MH - rho Guanine Nucleotide Dissociation Inhibitor alpha/metabolism PMC - PMC4749407 MID - NIHMS732109 OTO - NOTNLM OT - Androgen receptor OT - Breast cancer OT - Endocrine therapy resistance OT - Epidermal growth factor receptor OT - Estrogen receptor OT - Tamoxifen COIS- Conflict of interest: The authors declare that they have no financial conflict of interest. EDAT- 2015/10/22 06:00 MHDA- 2016/09/10 06:00 PMCR- 2016/11/01 CRDT- 2015/10/22 06:00 PHST- 2015/10/12 00:00 [received] PHST- 2015/10/13 00:00 [accepted] PHST- 2015/10/22 06:00 [entrez] PHST- 2015/10/22 06:00 [pubmed] PHST- 2016/09/10 06:00 [medline] PHST- 2016/11/01 00:00 [pmc-release] AID - 10.1007/s10549-015-3609-7 [pii] AID - 10.1007/s10549-015-3609-7 [doi] PST - ppublish SO - Breast Cancer Res Treat. 2015 Nov;154(2):225-37. doi: 10.1007/s10549-015-3609-7. Epub 2015 Oct 20.