Heat Shock Factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells

  1. Natalia Vydra  Is a corresponding author
  2. Patryk Janus
  3. Paweł Kuś
  4. Tomasz Stokowy
  5. Katarzyna Mrowiec
  6. Agnieszka Toma-Jonik
  7. Aleksandra Krzywon
  8. Alexander Jorge Cortez
  9. Bartosz Wojtaś
  10. Bartłomiej Gielniewski
  11. Roman Jaksik
  12. Marek Kimmel
  13. Wieslawa Widlak  Is a corresponding author
  1. Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Poland
  2. Silesian University of Technology, Poland
  3. University of Bergen, Norway
  4. Polish Academy of Sciences, Poland
  5. Rice University, United States

Abstract

Heat shock factor 1 (HSF1), a key regulator of transcriptional responses to proteotoxic stress, was linked to estrogen (E2) signaling through estrogen receptor α (ERα). We found that an HSF1 deficiency may decrease ERα level, attenuate the mitogenic action of E2, counteract E2-stimulated cell scattering, and reduce adhesion to collagens and cell motility in ER-positive breast cancer cells. The stimulatory effect of E2 on the transcriptome is largely weaker in HSF1-deficient cells, in part due to the higher basal expression of E2-dependent genes, which correlates with the enhanced binding of unliganded ERα to chromatin in such cells. HSF1 and ERα can cooperate directly in E2-stimulated regulation of transcription, and HSF1 potentiates the action of ERα through a mechanism involving chromatin reorganization. Furthermore, HSF1 deficiency may increase the sensitivity to hormonal therapy (4-hydroxytamoxifen) or CDK4/6 inhibitors (palbociclib). Analyses of data from the TCGA database indicate that HSF1 increases the transcriptome disparity in ER-positive breast cancer and can enhance the genomic action of ERα. Moreover, only in ER-positive cancers, an elevated HSF1 level is associated with metastatic disease.

Data availability

Sequencing data have been deposited in GEO under accession codes GSE159802, GSE159724 (scheduled to be released on Oct 21, 2021), and GSE186004 (scheduled to be released on Oct 13, 2022).

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Natalia Vydra

    Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
    For correspondence
    natalia.vydra@io.gliwice.pl
    Competing interests
    The authors declare that no competing interests exist.
  2. Patryk Janus

    Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
    Competing interests
    The authors declare that no competing interests exist.
  3. Paweł Kuś

    Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland
    Competing interests
    The authors declare that no competing interests exist.
  4. Tomasz Stokowy

    Department of Clinical Science, University of Bergen, Bergen, Norway
    Competing interests
    The authors declare that no competing interests exist.
  5. Katarzyna Mrowiec

    Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
    Competing interests
    The authors declare that no competing interests exist.
  6. Agnieszka Toma-Jonik

    Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
    Competing interests
    The authors declare that no competing interests exist.
  7. Aleksandra Krzywon

    Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4796-5478
  8. Alexander Jorge Cortez

    Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1284-2638
  9. Bartosz Wojtaś

    Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  10. Bartłomiej Gielniewski

    Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
    Competing interests
    The authors declare that no competing interests exist.
  11. Roman Jaksik

    Department of Systems Biology and Engineering, Silesian University of Technology, Gliwice, Poland
    Competing interests
    The authors declare that no competing interests exist.
  12. Marek Kimmel

    Department of Statistics, Rice University, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Wieslawa Widlak

    Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Gliwice, Poland
    For correspondence
    wieslawa.widlak@io.gliwice.pl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8440-9414

Funding

National Science Centre, Poland (2014/13/B/NZ7/02341)

  • Natalia Vydra

National Science Centre, Poland (2015/17/B/NZ3/03760)

  • Wieslawa Widlak

National Science Centre, Poland (2018/29/B/ST7/02550)

  • Marek Kimmel

European Social Fund (POWR.03.02.00-00-I029)

  • Paweł Kuś

European Social Fund (POWR.03.02.00-00-I029)

  • Alexander Jorge Cortez

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Maureen E Murphy, The Wistar Institute, United States

Publication history

  1. Received: April 28, 2021
  2. Preprint posted: May 7, 2021 (view preprint)
  3. Accepted: November 15, 2021
  4. Accepted Manuscript published: November 16, 2021 (version 1)
  5. Version of Record published: December 24, 2021 (version 2)

Copyright

© 2021, Vydra et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,258
    Page views
  • 255
    Downloads
  • 2
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Natalia Vydra
  2. Patryk Janus
  3. Paweł Kuś
  4. Tomasz Stokowy
  5. Katarzyna Mrowiec
  6. Agnieszka Toma-Jonik
  7. Aleksandra Krzywon
  8. Alexander Jorge Cortez
  9. Bartosz Wojtaś
  10. Bartłomiej Gielniewski
  11. Roman Jaksik
  12. Marek Kimmel
  13. Wieslawa Widlak
(2021)
Heat Shock Factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells
eLife 10:e69843.
https://doi.org/10.7554/eLife.69843

Further reading

    1. Cancer Biology
    Kexin Li, Qingji Huo ... Hiroki Yokota
    Research Article

    Osteosarcoma (OS) is the common primary bone cancer that affects mostly children and young adults. To augment the standard-of-care chemotherapy, we examined the possibility of protein-based therapy using mesenchymal stem cells (MSCs)-derived proteomes and OS-elevated proteins. While a conditioned medium (CM), collected from MSCs, did not present tumor-suppressing ability, the activation of PKA converted MSCs into induced tumor-suppressing cells (iTSCs). In a mouse model, the direct and hydrogel-assisted administration of CM inhibited tumor-induced bone destruction, and its effect was additive with cisplatin. CM was enriched with proteins such as calreticulin, which acted as an extracellular tumor suppressor by interacting with CD47. Notably, the level of CALR transcripts was elevated in OS tissues, together with other tumor-suppressing proteins, including histone H4, and PCOLCE. PCOLCE acted as an extracellular tumor-suppressing protein by interacting with amyloid precursor protein, a prognostic OS marker with poor survival. The results supported the possibility of employing a paradoxical strategy of utilizing OS transcriptomes for the treatment of OS.

    1. Biochemistry and Chemical Biology
    2. Cancer Biology
    Madeleine L Hart, Evan Quon ... Lucas B Sullivan
    Research Article Updated

    The oxidative tricarboxylic acid (TCA) cycle is a central mitochondrial pathway integrating catabolic conversions of NAD +to NADH and anabolic production of aspartate, a key amino acid for cell proliferation. Several TCA cycle components are implicated in tumorigenesis, including loss-of-function mutations in subunits of succinate dehydrogenase (SDH), also known as complex II of the electron transport chain (ETC), but mechanistic understanding of how proliferating cells tolerate the metabolic defects of SDH loss is still lacking. Here, we identify that SDH supports human cell proliferation through aspartate synthesis but, unlike other ETC impairments, the effects of SDH inhibition are not ameliorated by electron acceptor supplementation. Interestingly, we find aspartate production and cell proliferation are restored to SDH-impaired cells by concomitant inhibition of ETC complex I (CI). We determine that the benefits of CI inhibition in this context depend on decreasing mitochondrial NAD+/NADH, which drives SDH-independent aspartate production through pyruvate carboxylation and reductive carboxylation of glutamine. We also find that genetic loss or restoration of SDH selects for cells with concordant CI activity, establishing distinct modalities of mitochondrial metabolism for maintaining aspartate synthesis. These data therefore identify a metabolically beneficial mechanism for CI loss in proliferating cells and reveal how compartmentalized redox changes can impact cellular fitness.