Journal Article
. 2013 Nov; 73(23):6856-64.
doi: 10.1158/0008-5472.CAN-13-1197.

D538G mutation in estrogen receptor-α: A novel mechanism for acquired endocrine resistance in breast cancer

Keren Merenbakh-Lamin 1 Noa Ben-Baruch  Adva Yeheskel  Addie Dvir  Lior Soussan-Gutman  Rinath Jeselsohn  Roman Yelensky  Myles Brown  Vincent A Miller  David Sarid  Shulamith Rizel  Baruch Klein  Tami Rubinek  Ido Wolf  
Affiliations
  • PMID: 24217577
  •     149 citations

Abstract

Resistance to endocrine therapy occurs in virtually all patients with estrogen receptor α (ERα)-positive metastatic breast cancer, and is attributed to various mechanisms including loss of ERα expression, altered activity of coregulators, and cross-talk between the ERα and growth factor signaling pathways. To our knowledge, acquired mutations of the ERα have not been described as mediating endocrine resistance. Samples of 13 patients with metastatic breast cancer were analyzed for mutations in cancer-related genes. In five patients who developed resistance to hormonal therapy, a mutation of A to G at position 1,613 of ERα, resulting in a substitution of aspartic acid at position 538 to glycine (D538G), was identified in liver metastases. Importantly, the mutation was not detected in the primary tumors obtained prior to endocrine treatment. Structural modeling indicated that D538G substitution leads to a conformational change in the ligand-binding domain, which mimics the conformation of activated ligand-bound receptor and alters binding of tamoxifen. Indeed, experiments in breast cancer cells indicated constitutive, ligand-independent transcriptional activity of the D538G receptor, and overexpression of it enhanced proliferation and conferred resistance to tamoxifen. These data indicate a novel mechanism of acquired endocrine resistance in breast cancer. Further studies are needed to assess the frequency of D538G-ERα among patients with breast cancer and explore ways to inhibit its activity and restore endocrine sensitivity.

Drug resistance: making a point.
Nicola McCarthy.
Nat Rev Cancer, 2013 Nov 29; 14(1). PMID: 24285243
Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer.
Rinath Jeselsohn, Roman Yelensky, +28 authors, Vincent A Miller.
Clin Cancer Res, 2014 Jan 09; 20(7). PMID: 24398047    Free PMC article.
Highly Cited.
Estrogen receptor (ER) α mutations in breast cancer: hidden in plain sight.
Suzanne A W Fuqua, Guowei Gu, Yassine Rechoum.
Breast Cancer Res Treat, 2014 Feb 04; 144(1). PMID: 24487689    Free PMC article.
Review.
Defining the conformation of the estrogen receptor complex that controls estrogen-induced apoptosis in breast cancer.
Ifeyinwa Obiorah, Surojeet Sengupta, Ramona Curpan, V Craig Jordan.
Mol Pharmacol, 2014 Mar 13; 85(5). PMID: 24608856    Free PMC article.
Tumor heterogeneity confounds and illuminates: a case for Darwinian tumor evolution.
Kornelia Polyak.
Nat Med, 2014 Apr 09; 20(4). PMID: 24710378
Acquired resistance to selective estrogen receptor modulators (SERMs) in clinical practice (tamoxifen & raloxifene) by selection pressure in breast cancer cell populations.
Ping Fan, V Craig Jordan.
Steroids, 2014 Jun 17; 90. PMID: 24930824    Free PMC article.
Cancer therapy. Ex vivo culture of circulating breast tumor cells for individualized testing of drug susceptibility.
Min Yu, Aditya Bardia, +21 authors, Daniel A Haber.
Science, 2014 Jul 12; 345(6193). PMID: 25013076    Free PMC article.
Highly Cited.
Linking estrogen-induced apoptosis with decreases in mortality following long-term adjuvant tamoxifen therapy.
V Craig Jordan.
J Natl Cancer Inst, 2014 Oct 02; 106(11). PMID: 25269699    Free PMC article.
Estrogen receptor alpha prevents bladder cancer via INPP4B inhibited akt pathway in vitro and in vivo.
Iawen Hsu, Chiuan-Ren Yeh, +8 authors, Shuyuan Yeh.
Oncotarget, 2014 Oct 04; 5(17). PMID: 25277204    Free PMC article.
MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers.
Morassa Mohseni, Justin Cidado, +17 authors, Ben Ho Park.
Proc Natl Acad Sci U S A, 2014 Nov 26; 111(49). PMID: 25422431    Free PMC article.
NFκB affects estrogen receptor expression and activity in breast cancer through multiple mechanisms.
Jonna Frasor, Lamiaa El-Shennawy, Joshua D Stender, Irida Kastrati.
Mol Cell Endocrinol, 2014 Dec 03; 418 Pt 3. PMID: 25450861    Free PMC article.
Review.
Precision medicine in breast cancer: genes, genomes, and the future of genomically driven treatments.
Daniel G Stover, Nikhil Wagle.
Curr Oncol Rep, 2015 Feb 25; 17(4). PMID: 25708799    Free PMC article.
Review.
Clinical management of breast cancer heterogeneity.
Dimitrios Zardavas, Alexandre Irrthum, Charles Swanton, Martine Piccart.
Nat Rev Clin Oncol, 2015 Apr 22; 12(7). PMID: 25895611
Highly Cited. Review.
Mechanisms of aromatase inhibitor resistance.
Cynthia X Ma, Tomás Reinert, Izabela Chmielewska, Matthew J Ellis.
Nat Rev Cancer, 2015 Apr 25; 15(5). PMID: 25907219
Highly Cited. Review.
Estrogen receptor mutations and their role in breast cancer progression.
Prasanna G Alluri, Corey Speers, Arul M Chinnaiyan.
Breast Cancer Res, 2014 Jan 01; 16(6). PMID: 25928204    Free PMC article.
Review.
Down-regulation of programmed cell death 4 (PDCD4) is associated with aromatase inhibitor resistance and a poor prognosis in estrogen receptor-positive breast cancer.
Zhike Chen, Yate-Ching Yuan, +3 authors, Shiuan Chen.
Breast Cancer Res Treat, 2015 Jun 01; 152(1). PMID: 26026468    Free PMC article.
The molecular, cellular and clinical consequences of targeting the estrogen receptor following estrogen deprivation therapy.
Ping Fan, Philipp Y Maximov, +2 authors, V Craig Jordan.
Mol Cell Endocrinol, 2015 Jun 09; 418 Pt 3. PMID: 26052034    Free PMC article.
Review.
Positron emission tomography of tumour [(18)F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy.
Michel van Kruchten, Andor W J M Glaudemans, +3 authors, Geke A P Hospers.
Eur J Nucl Med Mol Imaging, 2015 Jun 21; 42(11). PMID: 26091705    Free PMC article.
ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer.
Rinath Jeselsohn, Gilles Buchwalter, +2 authors, Rachel Schiff.
Nat Rev Clin Oncol, 2015 Jul 01; 12(10). PMID: 26122181    Free PMC article.
Highly Cited. Review.
ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients.
David Chu, Costanza Paoletti, +26 authors, Ben Ho Park.
Clin Cancer Res, 2015 Aug 12; 22(4). PMID: 26261103    Free PMC article.
Highly Cited.
The changing role of ER in endocrine resistance.
Agostina Nardone, Carmine De Angelis, +2 authors, Rachel Schiff.
Breast, 2015 Aug 15; 24 Suppl 2. PMID: 26271713    Free PMC article.
Review.
Prognostic role of PIK3CA mutations of cell-free DNA in early-stage triple negative breast cancer.
Takashi Takeshita, Yutaka Yamamoto, +5 authors, Hirotaka Iwase.
Cancer Sci, 2015 Sep 12; 106(11). PMID: 26353837    Free PMC article.
Endocrine resistance in breast cancer--An overview and update.
Robert Clarke, John J Tyson, J Michael Dixon.
Mol Cell Endocrinol, 2015 Oct 13; 418 Pt 3. PMID: 26455641    Free PMC article.
Highly Cited. Review.
Sensitive Detection of Mono- and Polyclonal ESR1 Mutations in Primary Tumors, Metastatic Lesions, and Cell-Free DNA of Breast Cancer Patients.
Peilu Wang, Amir Bahreini, +19 authors, Steffi Oesterreich.
Clin Cancer Res, 2015 Oct 27; 22(5). PMID: 26500237    Free PMC article.
Highly Cited.
Optimal management of hormone receptor positive metastatic breast cancer in 2016.
Tomas Reinert, Carlos H Barrios.
Ther Adv Med Oncol, 2015 Nov 12; 7(6). PMID: 26557899    Free PMC article.
Review.
Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer.
Gaia Schiavon, Sarah Hrebien, +14 authors, Nicholas C Turner.
Sci Transl Med, 2015 Nov 13; 7(313). PMID: 26560360    Free PMC article.
Highly Cited.
Revealing the Complexity of Breast Cancer by Next Generation Sequencing.
John Verigos, Angeliki Magklara.
Cancers (Basel), 2015 Nov 13; 7(4). PMID: 26561834    Free PMC article.
Review.
Cell-free circulating tumour DNA as a liquid biopsy in breast cancer.
Leticia De Mattos-Arruda, Carlos Caldas.
Mol Oncol, 2016 Jan 19; 10(3). PMID: 26776681    Free PMC article.
Review.
Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation.
Sean W Fanning, Christopher G Mayne, +13 authors, Geoffrey L Greene.
Elife, 2016 Feb 03; 5. PMID: 26836308    Free PMC article.
Highly Cited.
Mechanisms of oestrogen receptor (ER) gene regulation in breast cancer.
J S Carroll.
Eur J Endocrinol, 2016 Feb 18; 175(1). PMID: 26884552    Free PMC article.
Review.
ELF5 and DOK7 regulation in anti-estrogen treated cells and tumors.
Lily M Fitzgerald, Eva P Browne, +7 authors, Kathleen F Arcaro.
Cancer Cell Int, 2016 Feb 18; 16. PMID: 26884724    Free PMC article.
Stapled Peptides with γ-Methylated Hydrocarbon Chains for the Estrogen Receptor/Coactivator Interaction.
Thomas E Speltz, Sean W Fanning, +4 authors, Terry W Moore.
Angew Chem Int Ed Engl, 2016 Mar 02; 55(13). PMID: 26928945    Free PMC article.
How drug resistance takes shape.
Rinath Jeselsohn, Myles Brown.
Elife, 2016 Mar 25; 5. PMID: 27010172    Free PMC article.
A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2- Metastatic Breast Cancer.
Ingrid A Mayer, Vandana G Abramson, +11 authors, Carlos L Arteaga.
Clin Cancer Res, 2016 Apr 30; 23(1). PMID: 27126994    Free PMC article.
Highly Cited.
Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant.
Jill M Spoerke, Steven Gendreau, +13 authors, Mark R Lackner.
Nat Commun, 2016 May 14; 7. PMID: 27174596    Free PMC article.
Highly Cited.
Estrogen regulates miRNA expression: implication of estrogen receptor and miR-124/AKT2 in tumor growth and angiogenesis.
Cheng-Fei Jiang, Dong-Mei Li, +10 authors, Bing-Hua Jiang.
Oncotarget, 2016 May 14; 7(24). PMID: 27175587    Free PMC article.
ESR1 mutations affect anti-proliferative responses to tamoxifen through enhanced cross-talk with IGF signaling.
Luca Gelsomino, Guowei Gu, +8 authors, Suzanne A W Fuqua.
Breast Cancer Res Treat, 2016 May 15; 157(2). PMID: 27178332    Free PMC article.
Mutation Analysis of Cell-Free DNA and Single Circulating Tumor Cells in Metastatic Breast Cancer Patients with High Circulating Tumor Cell Counts.
Jacqueline A Shaw, David S Guttery, +11 authors, R Charles Coombes.
Clin Cancer Res, 2016 Nov 05; 23(1). PMID: 27334837    Free PMC article.
Highly Cited.
Anticipatory UPR Activation: A Protective Pathway and Target in Cancer.
David J Shapiro, Mara Livezey, +2 authors, Neal Andruska.
Trends Endocrinol Metab, 2016 Jun 30; 27(10). PMID: 27354311    Free PMC article.
Review.
Recurrent and pathological gene fusions in breast cancer: current advances in genomic discovery and clinical implications.
Jamunarani Veeraraghavan, Jiacheng Ma, Yiheng Hu, Xiao-Song Wang.
Breast Cancer Res Treat, 2016 Jul 04; 158(2). PMID: 27372070    Free PMC article.
Review.
COPS5 amplification and overexpression confers tamoxifen-resistance in ERα-positive breast cancer by degradation of NCoR.
Renquan Lu, Xiaobo Hu, +9 authors, Lin Guo.
Nat Commun, 2016 Jul 05; 7. PMID: 27375289    Free PMC article.
The selective estrogen receptor downregulator GDC-0810 is efficacious in diverse models of ER+ breast cancer.
James D Joseph, Beatrice Darimont, +43 authors, Jeffrey H Hager.
Elife, 2016 Jul 14; 5. PMID: 27410477    Free PMC article.
Effective combination therapies in preclinical endocrine resistant breast cancer models harboring ER mutations.
Brendon Ladd, Anne Marie Mazzola, +17 authors, Celina M D'Cruz.
Oncotarget, 2016 Jul 30; 7(34). PMID: 27472462    Free PMC article.
The Estrogen Receptor α-Cistrome Beyond Breast Cancer.
Marjolein Droog, Mark Mensink, Wilbert Zwart.
Mol Endocrinol, 2016 Aug 05; 30(10). PMID: 27489947    Free PMC article.
Review.
Tamoxifen Resistance: Emerging Molecular Targets.
Milena Rondón-Lagos, Victoria E Villegas, +2 authors, Peter G Zaphiropoulos.
Int J Mol Sci, 2016 Aug 23; 17(8). PMID: 27548161    Free PMC article.
Review.
Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital.
Aditya Bardia, John A Iafrate, +2 authors, Valentina Nardi.
Oncologist, 2016 Aug 24; 21(9). PMID: 27551012    Free PMC article.
Blockade of the Hedgehog pathway downregulates estrogen receptor alpha signaling in breast cancer cells.
Yumei Diao, Ani Azatyan, +4 authors, Peter G Zaphiropoulos.
Oncotarget, 2016 Oct 01; 7(44). PMID: 27689403    Free PMC article.
Patient-derived tumour xenografts for breast cancer drug discovery.
John W Cassidy, Ankita S Batra, Wendy Greenwood, Alejandra Bruna.
Endocr Relat Cancer, 2016 Oct 22; 23(12). PMID: 27702751    Free PMC article.
Review.
Antiestrogen Resistant Cell Lines Expressing Estrogen Receptor α Mutations Upregulate the Unfolded Protein Response and are Killed by BHPI.
Chengjian Mao, Mara Livezey, Ji Eun Kim, David J Shapiro.
Sci Rep, 2016 Oct 08; 6. PMID: 27713477    Free PMC article.
Antiestrogens: structure-activity relationships and use in breast cancer treatment.
T Traboulsi, M El Ezzy, J L Gleason, S Mader.
J Mol Endocrinol, 2016 Oct 13; 58(1). PMID: 27729460    Free PMC article.
Review.
Genomic modelling of the ESR1 Y537S mutation for evaluating function and new therapeutic approaches for metastatic breast cancer.
A Harrod, J Fulton, +16 authors, S Ali.
Oncogene, 2016 Oct 18; 36(16). PMID: 27748765    Free PMC article.
Highly Cited.
Are Estrogen Receptor Genomic Aberrations Predictive of Hormone Therapy Response in Breast Cancer?
Sanaz Tabarestani, Marzieh Motallebi, Mohammad Esmaeil Akbari.
Iran J Cancer Prev, 2016 Oct 21; 9(4). PMID: 27761212    Free PMC article.
Review.
Epigenetic activation of the prostaglandin receptor EP4 promotes resistance to endocrine therapy for breast cancer.
J F Hiken, J I McDonald, +8 authors, J R Edwards.
Oncogene, 2016 Nov 22; 36(16). PMID: 27869171    Free PMC article.
Deciphering the divergent roles of progestogens in breast cancer.
Jason S Carroll, Theresa E Hickey, +2 authors, Wayne D Tilley.
Nat Rev Cancer, 2016 Nov 26; 17(1). PMID: 27885264
Review.
Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists.
Weiyi Toy, Hazel Weir, +17 authors, Sarat Chandarlapaty.
Cancer Discov, 2016 Dec 18; 7(3). PMID: 27986707    Free PMC article.
Highly Cited.
Detection fidelity of AR mutations in plasma derived cell-free DNA.
Alexa Goldstein, Patricia Valda Toro, +20 authors, Paula J Hurley.
Oncotarget, 2017 Feb 06; 8(9). PMID: 28152506    Free PMC article.
Clinical Implications of ESR1 Mutations in Hormone Receptor-Positive Advanced Breast Cancer.
Tomas Reinert, Everardo D Saad, Carlos H Barrios, José Bines.
Front Oncol, 2017 Apr 01; 7. PMID: 28361033    Free PMC article.
Review.
Role of steroid receptor and coregulator mutations in hormone-dependent cancers.
Anna C Groner, Myles Brown.
J Clin Invest, 2017 Apr 04; 127(4). PMID: 28368289    Free PMC article.
Review.
The Evolving Role of the Estrogen Receptor Mutations in Endocrine Therapy-Resistant Breast Cancer.
Rinath Jeselsohn, Carmine De Angelis, Myles Brown, Rachel Schiff.
Curr Oncol Rep, 2017 Apr 05; 19(5). PMID: 28374222
Review.
Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations.
David Brown, Dominiek Smeets, +18 authors, Christine Desmedt.
Nat Commun, 2017 Apr 22; 8. PMID: 28429735    Free PMC article.
Highly Cited.
Liquid biopsy: unlocking the potentials of cell-free DNA.
David Chu, Ben Ho Park.
Virchows Arch, 2017 May 04; 471(2). PMID: 28466157
Review.
Advances in systemic therapy for metastatic breast cancer: future perspectives.
S P Corona, N Sobhani, +5 authors, D Generali.
Med Oncol, 2017 May 21; 34(7). PMID: 28526922
Review.
Mutation site and context dependent effects of ESR1 mutation in genome-edited breast cancer cell models.
Amir Bahreini, Zheqi Li, +11 authors, Steffi Oesterreich.
Breast Cancer Res, 2017 May 26; 19(1). PMID: 28535794    Free PMC article.
Highly Cited.
Intrinsic ubiquitin E3 ligase activity of histone acetyltransferase Hbo1 for estrogen receptor α.
Masayoshi Iizuka, Takao Susa, +2 authors, Tomoki Okazaki.
Proc Jpn Acad Ser B Phys Biol Sci, 2017 Aug 05; 93(7). PMID: 28769019    Free PMC article.
Comparison of ESR1 Mutations in Tumor Tissue and Matched Plasma Samples from Metastatic Breast Cancer Patients.
Takashi Takeshita, Yutaka Yamamoto, +5 authors, Hirotaka Iwase.
Transl Oncol, 2017 Aug 05; 10(5). PMID: 28778025    Free PMC article.
Estrogen receptor coregulator binding modulators (ERXs) effectively target estrogen receptor positive human breast cancers.
Ganesh V Raj, Gangadhara Reddy Sareddy, +15 authors, Ratna K Vadlamudi.
Elife, 2017 Aug 09; 6. PMID: 28786813    Free PMC article.
Genomic profiling of ER+ breast cancers after short-term estrogen suppression reveals alterations associated with endocrine resistance.
Jennifer M Giltnane, Katherine E Hutchinson, +32 authors, Carlos L Arteaga.
Sci Transl Med, 2017 Aug 11; 9(402). PMID: 28794284    Free PMC article.
Estrogen receptor (ESR1) mutation in bone metastases from breast cancer.
Stephan Bartels, Matthias Christgen, +4 authors, Hans Kreipe.
Mod Pathol, 2017 Aug 12; 31(1). PMID: 28799536
Detection of ESR1 mutations in circulating cell-free DNA from patients with metastatic breast cancer treated with palbociclib and letrozole.
Rekha Gyanchandani, Karthik J Kota, +6 authors, Shannon L Puhalla.
Oncotarget, 2016 Aug 19; 8(40). PMID: 28978004    Free PMC article.
Prevalence of ESR1 E380Q mutation in tumor tissue and plasma from Japanese breast cancer patients.
Takashi Takeshita, Yutaka Yamamoto, +5 authors, Hirotaka Iwase.
BMC Cancer, 2017 Nov 24; 17(1). PMID: 29166868    Free PMC article.
Discovery of naturally occurring ESR1 mutations in breast cancer cell lines modelling endocrine resistance.
Lesley-Ann Martin, Ricardo Ribas, +25 authors, Mitch Dowsett.
Nat Commun, 2017 Dec 02; 8(1). PMID: 29192207    Free PMC article.
Comprehensive Mutation and Copy Number Profiling in Archived Circulating Breast Cancer Tumor Cells Documents Heterogeneous Resistance Mechanisms.
Costanza Paoletti, Andi K Cani, +24 authors, Scott A Tomlins.
Cancer Res, 2017 Dec 14; 78(4). PMID: 29233927    Free PMC article.
Are We Ready to Use ESR1 Mutations in Clinical Practice?
Rinath Jeselsohn.
Breast Care (Basel), 2017 Dec 14; 12(5). PMID: 29234250    Free PMC article.
Review.
Circulating Tumour Cells, Circulating Tumour DNA and Circulating MicroRNA in Metastatic Breast Carcinoma - What is the Role of Liquid Biopsy in Breast Cancer?
Arkadius Polasik, Marie Tzschaschel, +10 authors, Tanja Fehm.
Geburtshilfe Frauenheilkd, 2017 Dec 23; 77(12). PMID: 29269956    Free PMC article.
Nuclear receptors in cancer - uncovering new and evolving roles through genomic analysis.
Vineet K Dhiman, Michael J Bolt, Kevin P White.
Nat Rev Genet, 2017 Dec 28; 19(3). PMID: 29279606
Review.
Clinically Observed Estrogen Receptor Alpha Mutations within the Ligand-Binding Domain Confer Distinguishable Phenotypes.
Shanhang Jia, Mark T Miedel, +13 authors, Andrew M Stern.
Oncology, 2018 Jan 08; 94(3). PMID: 29306943    Free PMC article.
A Computational Assay of Estrogen Receptor α Antagonists Reveals the Key Common Structural Traits of Drugs Effectively Fighting Refractory Breast Cancers.
Matic Pavlin, Angelo Spinello, +5 authors, Alessandra Magistrato.
Sci Rep, 2018 Jan 14; 8(1). PMID: 29330437    Free PMC article.
Break Breast Cancer Addiction by CRISPR/Cas9 Genome Editing.
Haitao Yang, MariaLynn Jaeger, +3 authors, Tao Weitao.
J Cancer, 2018 Jan 19; 9(2). PMID: 29344267    Free PMC article.
Review.
Allele-Specific Chromatin Recruitment and Therapeutic Vulnerabilities of ESR1 Activating Mutations.
Rinath Jeselsohn, Johann S Bergholz, +23 authors, Myles Brown.
Cancer Cell, 2018 Feb 14; 33(2). PMID: 29438694    Free PMC article.
Highly Cited.
Oncoprotein HBXIP enhances HOXB13 acetylation and co-activates HOXB13 to confer tamoxifen resistance in breast cancer.
Bowen Liu, Tianjiao Wang, +8 authors, Lihong Ye.
J Hematol Oncol, 2018 Feb 24; 11(1). PMID: 29471853    Free PMC article.
Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance.
John A Katzenellenbogen, Christopher G Mayne, +2 authors, Sarat Chandarlapaty.
Nat Rev Cancer, 2018 Apr 18; 18(6). PMID: 29662238    Free PMC article.
Highly Cited. Review.
Implications of ESR1 Mutations in Hormone Receptor-Positive Breast Cancer.
Tomás Reinert, Rodrigo Gonçalves, José Bines.
Curr Treat Options Oncol, 2018 Apr 19; 19(5). PMID: 29666928
Review.
Practical consensus recommendations regarding the use of hormonal therapy in metastatic breast cancer.
Senthil Rajappa, J Bajpai, +8 authors, S Aggarwal.
South Asian J Cancer, 2018 May 04; 7(2). PMID: 29721481    Free PMC article.
The Impact of ESR1 Mutations on the Treatment of Metastatic Breast Cancer.
Sasha M Pejerrey, Derek Dustin, +3 authors, Suzanne A W Fuqua.
Horm Cancer, 2018 May 08; 9(4). PMID: 29736566
Review.
Proteomic profiling identifies key coactivators utilized by mutant ERα proteins as potential new therapeutic targets.
Leah A Gates, Guowei Gu, +22 authors, Charles E Foulds.
Oncogene, 2018 May 12; 37(33). PMID: 29748621    Free PMC article.
Precision Medicine in Hormone Receptor-Positive Breast Cancer.
Azadeh Nasrazadani, Roby A Thomas, Steffi Oesterreich, Adrian V Lee.
Front Oncol, 2018 May 22; 8. PMID: 29780747    Free PMC article.
Review.
Enhanced ZnR/GPR39 Activity in Breast Cancer, an Alternative Trigger of Signaling Leading to Cell Growth.
Hila Ventura-Bixenshpaner, Hila Asraf, +4 authors, Michal Hershfinkel.
Sci Rep, 2018 May 29; 8(1). PMID: 29802348    Free PMC article.
A New Role for Estrogen Receptor α in Cell Proliferation and Cancer: Activating the Anticipatory Unfolded Protein Response.
Mara Livezey, Ji Eun Kim, David J Shapiro.
Front Endocrinol (Lausanne), 2018 Jul 03; 9. PMID: 29963013    Free PMC article.
Review.
Overcoming Therapeutic Resistance of Triple Positive Breast Cancer with CDK4/6 Inhibition.
Troy B Schedin, Virginia F Borges, Elena Shagisultanova.
Int J Breast Cancer, 2018 Jul 19; 2018. PMID: 30018827    Free PMC article.
Review.
Clinical value of circulating ESR1 mutations for patients with metastatic breast cancer: a meta-analysis.
Kai Zhang, Ruoxi Hong, +8 authors, Shusen Wang.
Cancer Manag Res, 2018 Aug 28; 10. PMID: 30147360    Free PMC article.
Review.
Signaling pathways and steroid receptors modulating estrogen receptor α function in breast cancer.
Rasmus Siersbæk, Sanjeev Kumar, Jason S Carroll.
Genes Dev, 2018 Sep 06; 32(17-18). PMID: 30181360    Free PMC article.
Review.
ESR1 mutations: Pièce de résistance.
Berry Button, Ben Ho Park.
Genes Dis, 2016 Apr 19; 3(2). PMID: 30258881    Free PMC article.
Review.
The predictive ability of plasma ESR1 mutations for the efficacy of endocrine therapy in hormone-receptor-positive advanced breast cancer.
Yangfan Du, Na Li, +2 authors, Shunchao Yan.
Onco Targets Ther, 2018 Oct 03; 11. PMID: 30275706    Free PMC article.
AFF3 upregulation mediates tamoxifen resistance in breast cancers.
Yawei Shi, Yang Zhao, +5 authors, Shenming Wang.
J Exp Clin Cancer Res, 2018 Oct 18; 37(1). PMID: 30326937    Free PMC article.
Mortality after breast cancer as a function of time since diagnosis by estrogen receptor status and age at diagnosis.
Harindra Jayasekara, Robert J MacInnis, +11 authors, John L Hopper.
Int J Cancer, 2019 Feb 17; 145(12). PMID: 30771221    Free PMC article.
ESR1 mutations in breast cancer.
Derek Dustin, Guowei Gu, Suzanne A W Fuqua.
Cancer, 2019 Jul 19; 125(21). PMID: 31318440    Free PMC article.
Review.
Bone Marrow Stromal Cells Transcriptionally Repress ESR1 but Cannot Overcome Constitutive ESR1 Mutant Activity.
David K Lung, Jay W Warrick, +4 authors, Elaine T Alarid.
Endocrinology, 2019 Sep 11; 160(10). PMID: 31504407    Free PMC article.
ERα-targeted endocrine therapy, resistance and the role of GPER.
Richard A Pepermans, Eric R Prossnitz.
Steroids, 2019 Sep 14; 152. PMID: 31518595    Free PMC article.
Review.
Non-canonical Estrogen Signaling in Endocrine Resistance.
Prathibha Ranganathan, Namratha Nadig, Sughosha Nambiar.
Front Endocrinol (Lausanne), 2019 Nov 22; 10. PMID: 31749762    Free PMC article.
Review.
New insights into acquired endocrine resistance of breast cancer.
Ping Fan, V Craig Jordan.
Cancer Drug Resist, 2019 Dec 10; 2. PMID: 31815253    Free PMC article.
Estrogen receptor coregulator binding modulator (ERX-11) enhances the activity of CDK4/6 inhibitors against estrogen receptor-positive breast cancers.
Suryavathi Viswanadhapalli, Shihong Ma, +17 authors, Ratna K Vadlamudi.
Breast Cancer Res, 2019 Dec 28; 21(1). PMID: 31878959    Free PMC article.
Association between ESR1, ESR2, HER2, UGT1A4, and UGT2B7 polymorphisms and breast Cancer in Jordan: a case-control study.
Laith N Al-Eitan, Doaa M Rababa'h, Mansour A Alghamdi, Rame H Khasawneh.
BMC Cancer, 2020 Jan 01; 19(1). PMID: 31888550    Free PMC article.
The Emerging Role of ESR1 Mutations in Luminal Breast Cancer as a Prognostic and Predictive Biomarker of Response to Endocrine Therapy.
Irene De Santo, Amelia McCartney, +2 authors, Luca Malorni.
Cancers (Basel), 2019 Dec 05; 11(12). PMID: 31795152    Free PMC article.
Review.
Prevalence of ESR1 Mutation in Chinese ER-Positive Breast Cancer.
Wenzhen Zhu, Chongyang Ren, +3 authors, Ning Liao.
Onco Targets Ther, 2020 Feb 06; 13. PMID: 32021303    Free PMC article.
ESR1 mutations are frequent in newly diagnosed metastatic and loco-regional recurrence of endocrine-treated breast cancer and carry worse prognosis.
Adi Zundelevich, Maya Dadiani, +14 authors, Einav Nili Gal-Yam.
Breast Cancer Res, 2020 Feb 06; 22(1). PMID: 32014063    Free PMC article.
Dynamics Insights Into the Gain of Flexibility by Helix-12 in ESR1 as a Mechanism of Resistance to Drugs in Breast Cancer Cell Lines.
Abbas Khan, Ashfaq-Ur-Rehman, +7 authors, Dong-Qing Wei.
Front Mol Biosci, 2020 Feb 11; 6. PMID: 32039233    Free PMC article.
Mechanisms of resistance to estrogen receptor modulators in ER+/HER2- advanced breast cancer.
Jin Zhang, Qianying Wang, +3 authors, Zhengmao Zhu.
Cell Mol Life Sci, 2019 Sep 01; 77(4). PMID: 31471681
Review.
Immunohistochemical analysis of estrogen receptor in breast cancer with ESR1 mutations detected by hybrid capture-based next-generation sequencing.
Dara S Ross, Ahmet Zehir, +9 authors, Hannah Y Wen.
Mod Pathol, 2018 Aug 31; 32(1). PMID: 30158597    Free PMC article.
Antagonists for Constitutively Active Mutant Estrogen Receptors: Insights into the Roles of Antiestrogen-Core and Side-Chain.
Abhishek Sharma, Weiyi Toy, +10 authors, John A Katzenellenbogen.
ACS Chem Biol, 2018 Nov 09; 13(12). PMID: 30404440    Free PMC article.
Estrogen-independent Myc overexpression confers endocrine therapy resistance on breast cancer cells expressing ERαY537S and ERαD538G mutations.
Liqun Yu, Lawrence Wang, +7 authors, David J Shapiro.
Cancer Lett, 2018 Nov 13; 442. PMID: 30419347    Free PMC article.
Loss of function of NF1 is a mechanism of acquired resistance to endocrine therapy in lobular breast cancer.
E S Sokol, Y X Feng, +12 authors, R J Hartmaier.
Ann Oncol, 2018 Nov 14; 30(1). PMID: 30423024    Free PMC article.
The ER-alpha mutation Y537S confers Tamoxifen-resistance via enhanced mitochondrial metabolism, glycolysis and Rho-GDI/PTEN signaling: Implicating TIGAR in somatic resistance to endocrine therapy.
Marco Fiorillo, Rosa Sanchez-Alvarez, Federica Sotgia, Michael P Lisanti.
Aging (Albany NY), 2018 Dec 24; 10(12). PMID: 30573703    Free PMC article.
Estrogen Signaling in Endometrial Cancer: a Key Oncogenic Pathway with Several Open Questions.
Adriana C Rodriguez, Zannel Blanchard, Kathryn A Maurer, Jason Gertz.
Horm Cancer, 2019 Feb 04; 10(2-3). PMID: 30712080    Free PMC article.
Highly Cited. Review.
Comprehensive Genomic Analysis Reveals that the Pioneering Function of FOXA1 Is Independent of Hormonal Signaling.
Silvia-E Glont, Igor Chernukhin, Jason S Carroll.
Cell Rep, 2019 Mar 07; 26(10). PMID: 30840881    Free PMC article.
Role of Hedgehog Signaling in Breast Cancer: Pathogenesis and Therapeutics.
Natalia A Riobo-Del Galdo, Ángela Lara Montero, Eva V Wertheimer.
Cells, 2019 Apr 28; 8(4). PMID: 31027259    Free PMC article.
Review.
Steroid receptor/coactivator binding inhibitors: An update.
Kornelia J Skowron, Kenneth Booker, +7 authors, Terry W Moore.
Mol Cell Endocrinol, 2019 Jun 05; 493. PMID: 31163202    Free PMC article.
Review.
Estrogen-independent molecular actions of mutant estrogen receptor 1 in endometrial cancer.
Zannel Blanchard, Jeffery M Vahrenkamp, +2 authors, Jason Gertz.
Genome Res, 2019 Aug 01; 29(9). PMID: 31362937    Free PMC article.
The estrogen receptor-alpha S118P variant does not affect breast cancer incidence or response to endocrine therapies.
Berry Button, Sarah Croessmann, +18 authors, Ben Ho Park.
Breast Cancer Res Treat, 2018 Dec 19; 174(2). PMID: 30560461    Free PMC article.
Collective effects of long-range DNA methylations predict gene expressions and estimate phenotypes in cancer.
Soyeon Kim, Hyun Jung Park, Xiangqin Cui, Degui Zhi.
Sci Rep, 2020 Mar 05; 10(1). PMID: 32127627    Free PMC article.
Ventral prostate and mammary gland phenotype in mice with complete deletion of the ERβ gene.
Margaret Warner, Wan-Fu Wu, +3 authors, Jan-Ake Gustafsson.
Proc Natl Acad Sci U S A, 2020 Feb 23; 117(9). PMID: 32075916    Free PMC article.
G1T48, an oral selective estrogen receptor degrader, and the CDK4/6 inhibitor lerociclib inhibit tumor growth in animal models of endocrine-resistant breast cancer.
Kaitlyn J Andreano, Suzanne E Wardell, +15 authors, John D Norris.
Breast Cancer Res Treat, 2020 Mar 05; 180(3). PMID: 32130619    Free PMC article.
A single droplet digital PCR for ESR1 activating mutations detection in plasma.
Emmanuelle Jeannot, Lauren Darrigues, +13 authors, Charlotte Proudhon.
Oncogene, 2020 Feb 12; 39(14). PMID: 32042112
Progesterone Receptor Gene Variants in Metastatic Estrogen Receptor Positive Breast Cancer.
Amy M Fowler, Kelley Salem, +6 authors, Aparna M Mahajan.
Horm Cancer, 2020 Jan 17; 11(2). PMID: 31942683    Free PMC article.
Overcoming Endocrine Resistance in Breast Cancer.
Ariella B Hanker, Dhivya R Sudhan, Carlos L Arteaga.
Cancer Cell, 2020 Apr 15; 37(4). PMID: 32289273    Free PMC article.
Review.
Estrogen receptor mutations found in breast cancer metastases integrated with the molecular pharmacology of selective ER modulators.
V Craig Jordan, Ramona Curpan, Philipp Y Maximov.
J Natl Cancer Inst, 2015 Apr 04; 107(6). PMID: 25838462    Free PMC article.
Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells.
Abdulaziz B Hamid, Ruben C Petreaca.
Cancers (Basel), 2020 Apr 15; 12(4). PMID: 32283832    Free PMC article.
Review.
R269C variant of ESR1: high prevalence and differential function in a subset of pancreatic cancers.
Tomer Boldes, Keren Merenbakh-Lamin, +6 authors, Ido Wolf.
BMC Cancer, 2020 Jun 10; 20(1). PMID: 32513126    Free PMC article.
Discovery of GNE-149 as a Full Antagonist and Efficient Degrader of Estrogen Receptor alpha for ER+ Breast Cancer.
Jun Liang, Robert Blake, +30 authors, Xiaojing Wang.
ACS Med Chem Lett, 2020 Jun 20; 11(6). PMID: 32551022    Free PMC article.
Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer.
Annamaria Salvati, Valerio Gigantino, +8 authors, Giorgio Giurato.
Int J Mol Sci, 2020 Jun 11; 21(11). PMID: 32517194    Free PMC article.
Review.
Computer-Aided Ligand Discovery for Estrogen Receptor Alpha.
Divya Bafna, Fuqiang Ban, +2 authors, Artem Cherkasov.
Int J Mol Sci, 2020 Jun 18; 21(12). PMID: 32545494    Free PMC article.
Review.
Invasive Lobular Breast Cancer as a Distinct Disease: Implications for Therapeutic Strategy.
Jocelyn Luveta, Ruth M Parks, +2 authors, Simon J Johnston.
Oncol Ther, 2020 Jul 24; 8(1). PMID: 32700069    Free PMC article.
Review.
Increased frequency of ESR1 mutation in metastatic breast cancer by dosing selective estrogen receptor modulator followed by aromatase inhibitor.
Kaoru Takeshima, Tetsu Hayashida, +5 authors, Yuko Kitagawa.
Oncol Lett, 2020 Jul 30; 20(2). PMID: 32724363    Free PMC article.
Endocrine Resistance in Hormone Receptor Positive Breast Cancer-From Mechanism to Therapy.
Aradhana Rani, Justin Stebbing, Georgios Giamas, John Murphy.
Front Endocrinol (Lausanne), 2019 Jun 11; 10. PMID: 31178825    Free PMC article.
Highly Cited. Review.
ESR1 alterations and metastasis in estrogen receptor positive breast cancer.
Jonathan T Lei, Xuxu Gou, Sinem Seker, Matthew J Ellis.
J Cancer Metastasis Treat, 2019 May 21; 5. PMID: 31106278    Free PMC article.
The Central Contributions of Breast Cancer Stem Cells in Developing Resistance to Endocrine Therapy in Estrogen Receptor (ER)-Positive Breast Cancer.
David Rodriguez, Marc Ramkairsingh, +3 authors, Damu Tang.
Cancers (Basel), 2019 Jul 25; 11(7). PMID: 31336602    Free PMC article.
Review.
Structural, Thermodynamic, and Kinetic Traits of Antiestrogen-Compounds Selectively Targeting the Y537S Mutant Estrogen Receptor α Transcriptional Activity in Breast Cancer Cell Lines.
Matic Pavlin, Luca Gelsomino, +4 authors, Alessandra Magistrato.
Front Chem, 2019 Sep 26; 7. PMID: 31552220    Free PMC article.
Currently Applied Molecular Assays for Identifying ESR1 Mutations in Patients with Advanced Breast Cancer.
Nuri Lee, Min-Jeong Park, +2 authors, Seri Jeong.
Int J Mol Sci, 2020 Nov 26; 21(22). PMID: 33233830    Free PMC article.
Review.
A Phase II Trial of Neoadjuvant MK-2206, an AKT Inhibitor, with Anastrozole in Clinical Stage II or III PIK3CA-Mutant ER-Positive and HER2-Negative Breast Cancer.
Cynthia X Ma, Vera Suman, +31 authors, Matthew J Ellis.
Clin Cancer Res, 2017 Sep 07; 23(22). PMID: 28874413    Free PMC article.
Resistance to endocrine therapy in breast cancer: molecular mechanisms and future goals.
Małgorzata Szostakowska, Alicja Trębińska-Stryjewska, Ewa Anna Grzybowska, Anna Fabisiewicz.
Breast Cancer Res Treat, 2018 Nov 02; 173(3). PMID: 30382472    Free PMC article.
Review.
Pathways to Endocrine Therapy Resistance in Breast Cancer.
Md Moquitul Haque, Kartiki V Desai.
Front Endocrinol (Lausanne), 2019 Sep 10; 10. PMID: 31496995    Free PMC article.
Review.
PI3K/AKT/mTOR Signaling Pathway in Breast Cancer: From Molecular Landscape to Clinical Aspects.
Daniela Miricescu, Alexandra Totan, +3 authors, Maria Greabu.
Int J Mol Sci, 2020 Dec 31; 22(1). PMID: 33375317    Free PMC article.
Review.
Recent progress in selective estrogen receptor downregulators (SERDs) for the treatment of breast cancer.
Shagufta, Irshad Ahmad, Shimy Mathew, Sofia Rahman.
RSC Med Chem, 2021 Jan 23; 11(4). PMID: 33479648    Free PMC article.
Review.
A Closer Look at Estrogen Receptor Mutations in Breast Cancer and Their Implications for Estrogen and Antiestrogen Responses.
Léa Clusan, Pascale Le Goff, Gilles Flouriot, Farzad Pakdel.
Int J Mol Sci, 2021 Jan 17; 22(2). PMID: 33451133    Free PMC article.
Review.
Estrogen Receptor Alpha Mutations in Breast Cancer Cells Cause Gene Expression Changes through Constant Activity and Secondary Effects.
Spencer Arnesen, Zannel Blanchard, +5 authors, Jason Gertz.
Cancer Res, 2020 Nov 14; 81(3). PMID: 33184109    Free PMC article.
Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer.
Aditi S Khatpe, Adedeji K Adebayo, +2 authors, Harikrishna Nakshatri.
Cancers (Basel), 2021 Jan 28; 13(3). PMID: 33498407    Free PMC article.
Review.
Molecular Biomarkers for Contemporary Therapies in Hormone Receptor-Positive Breast Cancer.
Allegra Freelander, Lauren J Brown, +4 authors, Elgene Lim.
Genes (Basel), 2021 Mar 07; 12(2). PMID: 33671468    Free PMC article.
Review.
ESR1 Gene Mutation in Hormone Receptor-Positive HER2-Negative Metastatic Breast Cancer Patients: Concordance Between Tumor Tissue and Circulating Tumor DNA Analysis.
Loredana Urso, Grazia Vernaci, +12 authors, Maria Vittoria Dieci.
Front Oncol, 2021 Mar 30; 11. PMID: 33777770    Free PMC article.
Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer.
Malin Dahlgren, Anthony M George, +13 authors, Lao H Saal.
JNCI Cancer Spectr, 2021 May 04; 5(2). PMID: 33937624    Free PMC article.
Lasofoxifene as a potential treatment for therapy-resistant ER-positive metastatic breast cancer.
Muriel Lainé, Sean W Fanning, +6 authors, Geoffrey L Greene.
Breast Cancer Res, 2021 May 14; 23(1). PMID: 33980285    Free PMC article.