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Complete elimination of estrogen receptor α by PROTAC estrogen receptor α degrader ERD-148 in breast cancer cells

  • Original Laboratory Investigation
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

Purpose

Estrogen Receptor α (ERα) is a well-established therapeutic target for Estrogen Receptor (ER)-positive breast cancers. Both Selective Estrogen Receptor Degraders (SERD) and PROTAC ER degraders are synthetic compounds suppressing the ER activity through the degradation of ER. However, the differences between SERD and PROTAC ER degraders are far from clear.

Methods

The effect of PROTAC ER degrader ERD-148 and SERD fulvestrant on protein degradation was evaluated by western blot analysis. The cell proliferation was tested by WST-8 assays and the gene expressions were assessed by gene microarray and real-time RT-PCR analysis after the compound treatment.

Results

ERD-148 is a potent and selective PROTAC ERα degrader. It degrades not only unphosphorylated ERα but also the phosphorylated ERα in the cells. In contrast, the SERD fulvestrant showed much-reduced degradation potency on the phosphorylated ERα. The more complete degradation of ERα by ERD-148 translates into a greater maximum cell growth inhibition. However, ERD-148 and fulvestrant share a similar gene regulation profile except for the variation of regulation potency. Further studies indicate that ERD-148 degrades the ERα in fulvestrant-resistant cells.

Conclusion

PROTAC ER degrader has a different mechanism of action compared to SERD which may be used in treating fulvestrant-resistant cancers.

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Data availability

Data are available upon request.

Abbreviations

ER:

Estrogen receptor

ERD:

Estrogen receptor degrader

FITC:

Fluorescein-5-isothiocyanate

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

Imax:

Maximum inhibition

PCR:

Polymerase chain reaction

PI:

Propidium iodide

PROTAC:

Proteolysis-targeting chimeras

PVDF:

Polyvinylidene difluoride

RIPA buffer:

Radioimmunoprecipitation assay buffer

SERD:

Selective estrogen receptor degraders

SERM:

Selective estrogen receptor modulators

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Acknowledgements

We thank the assistance of the Department of Internal Medicine at the University of Michigan for this study.

Funding

This study is supported by the University of Michigan Regional Comprehensive Metabolomics Resource Core Pilot and feasibility Grant (U24 DK097153).

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Authors and Affiliations

  1. Department of Internal Medicine, University of Michigan, G349B, 520 NCRC, 1600 Huron Parkway, Ann Arbor, MI, 48109, USA

    Biao Hu & Jiantao Hu

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  1. Biao Hu
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Contributions

BH designed and conducted the experiments, analyzed and interpreted the data, and wrote the manuscript. JH conducted the experiments and wrote the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Biao Hu.

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The authors declare that they have no competing interests.

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This study was performed in line with the principles of the Declaration of Helsinki. The use of animals and cell lines was conducted following the NIH guidelines in the USA.

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Hu, B., Hu, J. Complete elimination of estrogen receptor α by PROTAC estrogen receptor α degrader ERD-148 in breast cancer cells. Breast Cancer Res Treat 203, 383–396 (2024). https://doi.org/10.1007/s10549-023-07136-2

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  • DOI: https://doi.org/10.1007/s10549-023-07136-2

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