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.
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).
Heat Shock Factor 1 (HSF1) supports the ESR1 action in breast cancer (RNA-seq)NCBI Gene Expression Omnibus, GSE159802.
Heat Shock Factor 1 (HSF1) supports the ESR1 action in breast cancer (ChIP-seq)NCBI Gene Expression Omnibus, GSE159724.
Heat Shock Factor 1 (HSF1) regulares the ESR1 action in breast cancer (RNA-seq)NCBI Gene Expression Omnibus, GSE186004.
Heat Shock Factor 1 (HSF1) acquires transcriptional competence under 17b-estradiol in ERa-positive breast cancer cells [ChIP-seq]NCBI Gene Expression Omnibus, GSE137558.
- Natalia Vydra
- Wieslawa Widlak
- Marek Kimmel
- Paweł Kuś
- Alexander Jorge Cortez
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Maureen E Murphy, The Wistar Institute, United States
- Received: April 28, 2021
- Accepted: November 15, 2021
- Accepted Manuscript published: November 16, 2021 (version 1)
© 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.