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Title:
Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer | Breast Cancer Research and Treatment
Description:
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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Keywords {🔍}
cancer, breast, pubmed, article, google, scholar, cas, receptor, res, androgen, resistance, estrogen, rho, cells, growth, tamoxifen, activation, egfr, signaling, factor, central, activity, cell, kinase, supplementary, material, fuqua, expression, human, content, research, enzalutamide, therapy, dois, clin, privacy, cookies, erαpositive, tsimelzon, tam, gdiα, erα, phosphorylation, access, receptors, medicine, endocrine, treat, mitogenactivated, protein,
Topics {✒️}
er/her2-positive breast cancer month download article/chapter tamoxifen-resistant breast cancer mitogen-activated protein kinase erα-positive breast cancer estrogen receptor alpha steroid antagonist action α-positive breast cancer early breast cancer steroid receptor regulation unliganded estrogen receptor androgen receptor expression oestrogen receptor activity progesterone receptor-positive prostate cancer cells growth factor receptors tam-induced phosphorylation ar-mediated tam resistance enhancing endocrine therapy related subjects bidirectional cross talk full article pdf human breast cancer human breast cancers erα-positive cells ar-mediated egfr activation luca gelsomino cotargeting signaling pathways personalized cancer therapy breast cancer cells major driving factor breast cancer prognosis estrogen receptor tyrosine kinase inhibitor privacy choices/manage cookies androgen receptor clinical breast cancer tam-resistant tumors androgen-binding proteins growth factor breast cancer survival map kinase pathway nongenomic androgen actions prostate cancer rho gtpase pathway decreased rho gdiα cell proliferation natl cancer inst endocrine therapy /akt signaling routes
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headline:Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer
description: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.
datePublished:2015-10-20T00:00:00Z
dateModified:2015-10-20T00:00:00Z
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Androgen receptor
Epidermal growth factor receptor
Estrogen receptor
Breast cancer
Endocrine therapy resistance
Tamoxifen
Oncology
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headline:Androgen receptor promotes tamoxifen agonist activity by activation of EGFR in ERα-positive breast cancer
description: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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Androgen receptor
Epidermal growth factor receptor
Estrogen receptor
Breast cancer
Endocrine therapy resistance
Tamoxifen
Oncology
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