Modulating HSF1 levels impacts expression of the estrogen receptor α and antiestrogen response.

Maruhen Ad Silveira,Félix-Antoine Bérube-Simard,Maxime C Côté,Arnaud Droit,Éric Fournier,Tania Cuppens,Mickaël Leclercq,Steve Bilodeau,Christophe Tav

doi:10.26508/lsa.202000811

Maruhen Ad Silveira, Félix-Antoine Bérube-Simard + Show 7 more

Open Access

https://doi.org/10.26508/lsa.202000811

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Abstract

Master transcription factors control the transcriptional program and are essential to maintain cellular functions. Among them, steroid nuclear receptors, such as the estrogen receptor α (ERα), are central to the etiology of hormone-dependent cancers which are accordingly treated with corresponding endocrine therapies. However, resistance invariably arises. Here, we show that high levels of the stress response master regulator, the heat shock factor 1 (HSF1), are associated with antiestrogen resistance in breast cancer cells. Indeed, overexpression of HSF1 leads to ERα degradation, decreased expression of ERα-activated genes, and antiestrogen resistance. Furthermore, we demonstrate that reducing HSF1 levels reinstates expression of the ERα and restores response to antiestrogens. Last, our results establish a proof of concept that inhibition of HSF1, in combination with antiestrogens, is a valid strategy to tackle resistant breast cancers. Taken together, we are proposing a mechanism where high HSF1 levels interfere with the ERα-dependent transcriptional program leading to endocrine resistance in breast cancer.

Highlights

Transcription factors are powerful modulators of the gene expression program which are commonly misregulated in human cancers (Lee & Young, 2013; Bradner et al, 2017; Silveira & Bilodeau, 2018; Lambert et al, 2018)
Because heat shock factor 1 (HSF1) overexpression is associated with poor prognosis and shorter life expectancy for breast cancer patients (Santagata et al, 2011; Mendillo et al, 2012; Gokmen-Polar & Badve, 2016), we hypothesized that it was involved in the molecular etiology leading to antiestrogen resistance
The increase in transcription factors binding was associated with recruitment of MED1 and bromodomain-containing protein 4 (BRD4) (Fig 3G and H) and higher RNA levels (Fig 3E). These results suggest that the transcriptional program shifted toward HSF1 at the expanse of estrogen receptor α (ERα) when an antiestrogen selective pressure was applied on MCF7 cells

Summary

Introduction

Transcription factors are powerful modulators of the gene expression program which are commonly misregulated in human cancers (Lee & Young, 2013; Bradner et al, 2017; Silveira & Bilodeau, 2018; Lambert et al, 2018). Master transcription factors have the ability to impose a transcriptional program and to reprogram a cell state (Graf & Enver, 2009; Lee & Young, 2013; Lambert et al, 2018). A single master transcription factor has the dual ability to activate new and decommission old gene expression programs

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