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Liver tropism of ER mutant breast cancer is characterized by unique molecular changes and immune infiltration

  • Original Laboratory Investigation
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Abstract

Purpose

Hotspot estrogen receptor alpha (ER/ESR1) mutations are recognized as the driver for both endocrine resistance and metastasis in advanced ER-positive (ER+) breast cancer, but their contributions to metastatic organ tropism remain insufficiently understood. In this study, we aim to comprehensively profile the organotropic metastatic pattern for ESR1 mutant breast cancer.

Methods

The organ-specific metastatic pattern of ESR1 mutant breast cancer was delineated using multi-omics data from multiple publicly available cohorts of ER+ metastatic breast cancer patients. Gene mutation/copy number variation (CNV) and differential gene expression analyses were performed to identify the genomic and transcriptomic alterations uniquely associated with ESR1 mutant liver metastasis. Upstream regulator, downstream pathway, and immune infiltration analysis were conducted for subsequent mechanistic investigations.

Results

ESR1 mutation-driven liver tropism was revealed by significant differences, encompassing a higher prevalence of liver metastasis in patients with ESR1 mutant breast cancer and an enrichment of mutations in liver metastatic samples. The significant enrichment of AGO2 copy number amplifications (CNAs) and multiple gene expression changes were revealed uniquely in ESR1 mutant liver metastasis. We also unveiled alterations in downstream signaling pathways and immune infiltration, particularly an enrichment of neutrophils, suggesting potential therapeutic vulnerabilities.

Conclusion

Our data provide a comprehensive characterization of the behaviors and mechanisms of ESR1 mutant liver metastasis, paving the way for the development of personalized therapy to target liver metastasis for patients with ESR1 mutant breast cancer.

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Data availability

All data analyzed in this study have previously been reported [23, 31, 33, 37,38,39, 47, 71,72,73,74] and are publicly available. For genomic analysis, the genetic alterations and clinical characteristics in the studies by Nguyen et al. [33] and Razavi et al. [23] were downloaded from cBioPortal (https://www.cbioportal.org/) [35, 36]. The ESR1 genotype status and metastatic site information in the studies by Jeselsohn et al. [31], Pleasance et al. [38], Paul et al. [37], and Robinson et al. [39] were downloaded from the supplementary data of the published papers [30]. For transcriptomic analysis, the data from DFCI cohort have been described in previous publications [31, 47, 71,72,73,74] and deposited into the database of Genotypes and Phenotypes (dbGaP) with accession number phs001285.v1.p1. For the MET500 cohort [39], data were downloaded from USCS Xena (https://xenabrowser.net/) and are available from dbGaP with accession number phs000673.v4.p1. For the POG570 cohort [74], raw data were downloaded from the BCGSC portal. The codes used in R Studio were deposited to Code Ocean (https://codeocean.com/capsule/2246397/tree).

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Acknowledgements

Yang Wu was a former visiting research scholar at the University of Pittsburgh School of Medicine supported by funds from The China Scholarship Council and Tsinghua University.

Funding

This work was supported by the Initiative Scientific Research Program, Institute for Intelligent Healthcare, Tsinghua University (No. 12017C1024), and in part supported by an award from The Breasties (SO).

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Authors and Affiliations

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

    Yang Wu

  2. Women’s Cancer Research Center, UPMC Hillman Cancer Center, Magee-Womens Research Institute, Pittsburgh, PA, USA

    Yang Wu, Zheqi Li, Adrian V. Lee & Steffi Oesterreich

  3. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA

    Zheqi Li, Adrian V. Lee & Steffi Oesterreich

  4. Institute for Precision Medicine, University of Pittsburgh, Pittsburgh, PA, USA

    Adrian V. Lee

  5. Department of General Surgery, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China

    Bin Luo

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  1. Yang Wu
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  4. Steffi Oesterreich
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Contributions

YW contributed to conceptualization, data curation, software, formal analysis, validation, investigation, visualization, writing of the original draft, and writing, reviewing, and editing of the manuscript. ZL contributed to conceptualization, data curation, formal analysis, and writing, reviewing, and editing of the manuscript. AVL contributed to conceptualization, resources, investigation, writing of the original draft, and writing, reviewing, and editing of the manuscript. SO contributed to conceptualization, resources, investigation, writing of the original draft, and writing, reviewing, and editing of the manuscript. BL contributed to conceptualization, supervision, funding acquisition, investigation, writing of the original draft, writing, reviewing, and editing of the manuscript, and project administration.

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Correspondence to Bin Luo.

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Wu, Y., Li, Z., Lee, A.V. et al. Liver tropism of ER mutant breast cancer is characterized by unique molecular changes and immune infiltration. Breast Cancer Res Treat 205, 371–386 (2024). https://doi.org/10.1007/s10549-024-07255-4

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