Journal Article

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

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

2021

Overview

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.

• Publisher: Life Science Alliance,Life Science Alliance LLC
• Subject: Antiestrogens / Breast cancer / Cyclin-dependent kinases / Endocrine therapy / Estrogen receptors / Estrogens / Gene expression / Heat shock factors / HSF1 protein / Kinases / Ligands / Medical prognosis / Nuclear receptors / Proteins / Transcription factors