Heat shock factor 1 (HSF1) cooperates with estrogen receptor α (ERα) in the regulation of estrogen action in breast cancer cells.

Patryk Janus,Natalia Vydra,Paweł Kus,Roman Jaksik,Agnieszka Toma-Jonik,Wieslawa Widlak,Alexander Jorge Cortez,Bartłomiej Gielniewski,Marek Kimmel,Tomasz Stokowy,Bartosz Wojtas,Katarzyna Mrowiec,Aleksandra Krzywon

doi:10.7554/elife.69843

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 Cancer Genome Atlas 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.

Highlights

Breast cancer is the most common malignancy in women worldwide
We found that the kinetics of estrogen receptor α (ERα) activation in response to E2 treatment was similar in Heat shock factor 1 (HSF1)+ and HSF1− MCF7 cells, ERα and pS118 ERα levels were lower in HSF1− cells (Figure 3F)
The analysis focused on terms related to response to stimulus and protein processing, revealed that most of them reached the statistical significance of differences between estrogen receptors (ERs)+/HSF1high and ER−/HSF1high cases

Summary

Introduction

Breast cancer is the most common malignancy in women worldwide. Four clinically relevant molecular types are distinguished based on the expression of estrogen receptors (ERs) and HER2 (ERBB2). According to the widely accepted hypothesis, estrogens acting through ERα stimulate cell proliferation and can support the growth of cells harboring mutations which accumulate, resulting in cancer. Another hypothesis suggests the ERα-independent action of estrogens via their metabolites, which can exert genotoxic effects, contributing to cancer development (Yager and Davidson, 2006) (Pescatori et al, 2021). Hormonal therapies targeting either estrogen production (ie, aromatase inhibitors) or the hormone receptor itself such as selective ER modulators (SERMs; ie, tamoxifen) and selective ER degraders (SERDs; ie, fulvestrant) are widely used to block the mitogenic action of estrogens in patients with ER-positive breast cancer (Renoir, 2012) (Farcas et al, 2021), contributing to the decline in mortality from breast cancer in recent decades (Iwase et al, 2021)

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