Targeting unique ligand binding domain structural features downregulates DKK1 in Y537S ESR1 mutant breast cancer cells

Sep 23, 2026

Uploaded by Patrick

Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Estrogen receptor alpha (ERα) mutations arise under therapeutic pressure, and next-generation SERMs/SERDs can produce non-durable responses. The Y537S mutation in the ERα ligand binding domain drives resistance by altering structural energetics and reducing inhibitor binding while enabling neomorphic transcription. T6I-29 remodels signaling, and RNA sequencing shows neomorphic DKK1 downregulation, with DKK1 enriched in ER+ patient plasma versus healthy controls.

LanguageEnglish

CategoryHealthcare

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Abstract

Introduction

Young et al. Breast Cancer Research (2025) 27:10 [https://doi.org/10.1186/s13058-024-01945-z](https://doi.org/10.1186/s13058-024-01945-z) Breast Cancer Research RESEARCH Open Access Targeting unique ligand binding domain structural features downregulates DKK1 in Y537S ESR1 mutant breast cancer cells K. S. Young 1, G. R. Hancock 1, E. C. Fink 1, A. Zigrossi 1, B. Flowers 1, D. A. Cooper2, V. T. Nguyen2, M. C. Martinez 1, K. S. Mon 1, M. Bosland3, D. R. Zak 1, A. P. Runde 1, M. N. Sharifi4, I. Kastrati 1, D. D. L. Minh2, S. Kregel 1 and Sean W. Fanning 1* Abstract Resistance to endocrine therapies remains a major clinical hurdle in breast cancer. Mutations to estrogen receptor alpha (ERα) arise after continued therapeutic pressure. Next generation selective estrogen receptor modulatorsand degraders/downregulators (SERMs and SERDs) show clinical efficacy, but responses are often non-durable. A tyrosine to serine point mutation at position 537 in the ERα ligand binding domain (LBD) is among the most common and most pathogenic alteration in this setting. It enables endocrine therapy resistance by superceding intrinsic structural-energetic gatekeepers of ER hormone-dependence, it enhances metastatic burden by enabling neomorphic ER-dependent transcriptional programs, and it resists SERM and SERD inhibiton by reducing their binding affinities and abilities to antagonize transcriptional coregulator binding. However, a subset of SERMs and SERDs can achieve efficacy by adopting poses that force the mutation to engage in a new interaction that favors the therapeutic receptor antagonist conformation. We previously described a chemically unconventional SERM, T6I-29, that demonstrates significant anti-proliferative activities in Y537S ERα breast cancer cells. Here, we use a comprehensive suite of structural-biochemical, in vitro, and in vivo approaches to better T6I-29’s activities in breast cancer cells harboring Y537S ERα . RNA sequencing in cells treated with T6I-29 reveal s a neomorphicdownregulation of DKK1, a secreted glycoprotein known to play oncogenic roles in other cancers. Importantly, we find that DKK1 is significantly enriched in ER + breast cancer plasma compared to healthy controls. This study showshow new SERMs and SERDs can identify new therapeutic pathways in endocrine-resistant ER + breast cancers. *Correspondence: Sean W. Fanning [sfanning@luc.edu](sfanning@luc.edu) 1Department of Cancer Biology, Loyola University Chicago Stritch School of Medicine, Maywood, IL 50153, USA 2Department of Chemistry, Illinois Institute of Technology, Chicago, IL 60616, USA 3Department of Pathology, University of Illinois Chicago, Chicago, IL 60607, USA 4Department of Medicine, University of Wisconsin, Madison, WI 53705, USA Introduction Over 70% of breast cancers are classified by their expression of the nuclear hormone receptor estrogen receptor alpha (ERα), encoded by the ESR1 gene [1]. In these cases, the estrogenic steroid hormones bind to the receptor with high affinity, promoting transcriptional complex formation at enhancers and promoters that propels tumor cell proliferation, invasion, migration, and metastasis [2–5]. Hormone therapies target this transcriptiondriven pathology through direct and indirect effects on ERα [6, 7]. Aromatase inhibitors, such as anastrozole/ © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Co

FAQs

Why is endocrine therapy resistance a major hurdle in breast cancer?

Resistance persists because ERα mutations emerge after ongoing therapeutic pressure, undermining the effectiveness of hormone-targeted treatment strategies.

What is the significance of the ERα Y537S mutation?

Y537S in the ligand binding domain enables endocrine therapy resistance by changing receptor structure and binding/antagonist behavior, and it also supports neomorphic ER-dependent transcriptional programs.

How does the study connect T6I-29 treatment to DKK1?

Structural-biochemical, in vitro, and in vivo analyses show that T6I-29 induces neomorphic downregulation of the secreted glycoprotein DKK1, and DKK1 is enriched in ER+ breast cancer plasma compared with healthy controls.

Sep 23, 2026

Uploaded by Patrick