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Cited by 13Heat shock proteins researchEstrogen and related hormone effectsBreast Cancer Treatment Studies

Small molecule inhibitor targeting the Hsp70-Bim protein–protein interaction in estrogen receptor-positive breast cancer overcomes tamoxifen resistance

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Song, Ting, Zhang, Hong, Zhao, Qicheng, Hu, Zhiyuan, Wang, Ziqian, Song, Yang, Zhang, Zhichao·2024·Breast Cancer Research
DOI 10.1186/s13058-024-01790-0PMC PMC10895875
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Abstract

Introduction: Estrogen receptor (ER) positive patients compromise about 70% of breast cancers. Tamoxifen, an antagonist of ERα66 (the classic ER), is the most effective and the standard first-line drug. However, its efficacy is limited by the development of acquired resistance. Methods: A specific inhibitor of Hsp70-Bim protein–protein interaction (PPI), S1g-2, together with an inhibitor of Hsp70-Bag3 PPI, MKT-077 and an ATP-competitive inhibitor VER155008, were used as chemical tools. Cell viability assays, co-immunoprecipitation and gene knockdown were used to investigate the role of Hsp70 in tamoxifen resistance. A xenograft model was established in which tamoxifen-resistant breast cancer (MCF-7/TAM-R) cells maintained in the presence of 5 μM tamoxifen were subcutaneously inoculated. The anti-tumor efficiency of S1g-2 was measured after a daily injection of 0.8 mg/kg for 14 days. Results: It was revealed that Hsp70-Bim PPI protects ERα-positive breast cancer from tamoxifen-induced apoptosis through binding and stabilizing ERα36, rather than ERα66, resulting in sustained EGFR mRNA and protein expression. Disruption of Hsp70-Bim PPI and downregulation of ERα36 expression in tumor samples are consistent with the in vitro functions of S1g-2, resulting in about a three-fold reduction in tumor volume. Conclusions: The in vivo activity and safety of S1g-2 illustrated that it is a potential strategy for Hsp70-Bim disruption to overcome tamoxifen-resistant ER-positive breast cancer.

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  • An increasing number of endocrine-resistance mechanisms have been characterized, and several small molecules have been reported to overcome Tamoxifen resistance.

    “An increasing number of endocrine-resistance mechanisms have been characterized, and several small molecules have been reported to overcome Tamoxifen resistance58,59.”

    From Harnessing artificial intelligence to identify Bufalin as a molecular glue degrader of estrogen receptor alpha (2025) · cites this paper as [58]

    The Introduction (page not provided) describes multiple pathways involved in tamoxifen resistance, and the Results (page not provided) report that the small molecule S1g-2 could overcome resistance in the tested breast cancer cells. The paper does not support the claim that several small molecules overcome resistance: its Results say MKT-077 did not, and VER-155008 showed no synergy with tamoxifen. (LLM, conf=0.88)

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Research works printed but not linked: 34

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Cited by

Sorted by citations

Authors
Song, T., Zhang, H., Zhao, Q., Hu, Z., Wang, Z., Song, Y., & Zhang, Z.
Affiliations
  • Dalian University of Technology (CN)
  • Tongji University (CN)
Corresponding author
  • Song, Ting
  • Zhang, Zhichao
ORCID
Venue
Breast Cancer Research
Publisher
Springer Science and Business Media LLC
Published
2024-02-26
Volume
26
Issue
1
Pages
33-33
ISSN
  • 1465-5411 (ISSN-L)
  • 1465-542X
DOI
10.1186/s13058-024-01790-0
PMC
PMC10895875
OpenAlex
W4392157314
Cited by
13
References
0
Citations by year
2026: 3 · 2025: 9 · 2024: 1
FWCI
1.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Breast Cancer Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
National Natural Science Foundation of China (82270186, 82073703, 82273778)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
Keywords
HSP70, building information modeling, protein-protein interaction inhibitors, tamoxifen resistance, estrogen receptor-positive breast cancer, ERα36, apoptosis, EGFR expression, MKT-077, small molecule inhibitors
MeSH terms
Bcl-2-Like Protein 11, Breast Neoplasms, Female, Humans, Tamoxifen, Gene Expression Regulation, Neoplastic, Drug Resistance, Neoplasm, Cell Line, Tumor, Estrogen Receptor alpha

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