FOXA1 Reprogramming Dictates Retinoid X Receptor Response in ESR1-Mutant Breast Cancer

Author:

Wu Yang12ORCID,Li Zheqi23ORCID,Wedn Abdalla M.23ORCID,Casey Allison N.23ORCID,Brown Daniel4ORCID,Rao Shalini V.5ORCID,Omarjee Soleilmane5ORCID,Hooda Jagmohan23ORCID,Carroll Jason S.5ORCID,Gertz Jason6ORCID,Atkinson Jennifer M.234ORCID,Lee Adrian V.234ORCID,Oesterreich Steffi23ORCID

Affiliation:

1. 1School of Medicine, Tsinghua University, Beijing, China.

2. 2Women's Cancer Research Center, UPMC Hillman Cancer Center, Magee-Women's Research Institute, Pittsburgh, Pennsylvania.

3. 3Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.

4. 4Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.

5. 5Cancer Research UK, Cambridge Institute, University of Cambridge, Cambridge, United Kingdom.

6. 6Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.

Abstract

Abstract Estrogen receptor alpha (ER/ESR1) mutations occur in 30% to 40% of endocrine resistant ER-positive (ER+) breast cancer. Forkhead box A1 (FOXA1) is a key pioneer factor mediating ER–chromatin interactions and endocrine response in ER+ breast cancer, but its role in ESR1-mutant breast cancer remains unclear. Our previous FOXA1 chromatin immunoprecipitation sequencing (ChIP-seq) identified a large portion of redistributed binding sites in T47D genome-edited Y537S and D538G ESR1–mutant cells. Here, we further integrated FOXA1 genomic binding profile with the isogenic ER cistrome, accessible genome, and transcriptome data of T47D cell model. FOXA1 redistribution was significantly associated with transcriptomic alterations caused by ESR1 mutations. Furthermore, in ESR1-mutant cells, FOXA1-binding sites less frequently overlapped with ER, and differential gene expression was less associated with the canonical FOXA1–ER axis. Motif analysis revealed a unique enrichment of retinoid X receptor (RXR) motifs in FOXA1-binding sites of ESR1-mutant cells. Consistently, ESR1-mutant cells were more sensitive to growth stimulation with the RXR agonist LG268. The mutant-specific response was dependent on two RXR isoforms, RXR-α and RXR-β, with a stronger dependency on the latter. In addition, T3, the agonist of thyroid receptor (TR) also showed a similar growth-promoting effect in ESR1-mutant cells. Importantly, RXR antagonist HX531 blocked growth of ESR1-mutant cells and a patient-derived xenograft (PDX)-derived organoid with an ESR1 D538G mutation. Collectively, our data support the evidence for a stronger RXR response associated with FOXA1 reprograming in ESR1-mutant cells, suggesting development of therapeutic strategies targeting RXR pathways in breast tumors with ESR1 mutation. Implications: It provides comprehensive characterization of the role of FOXA1 in ESR1-mutant breast cancer and potential therapeutic strategy through blocking RXR activation.

Funder

National Cancer Institute

Breast Cancer Research Foundation

Magee-Womens Research Institute

Nicole Miloche Foundation

Pennsylvania Breast Cancer Coalition

Shear Family Foundation

Susan G. Komen

John S. Lazo Cancer Pharmacology Fellowship

U.S. Department of Defense

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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