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

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.

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

“…A significant association between high HSF1 expression and increased mortality among the ER-positive breast cancer patients receiving hormonal therapy was first noticed by Santagata et al, 2011 , then confirmed by Gökmen-Polar and Badve, 2016 . It was proposed that overexpression of HSF1 in ER-positive breast cancers was associated with a decreased dependency on the ERα-controlled transcriptional program for cancer growth ( Silveira et al, 2021 ). However, this conclusion was based on experiments performed without estrogen stimulation.…”

Heat Shock Factor 1 (HSF1) as a new tethering factor for ESR1 supporting its action in breast cancer

“…Estrogen-dependent cancers are treated with hormonal therapies, and high levels of HSF1 have been associated with antiestrogen resistance (Silveira et al, 2021). It was proposed that overexpression of HSF1 in ER-positive breast cancers was associated with a decreased dependency on the ERα-controlled transcriptional program for cancer growth.…”

Heat Shock Proteins and HSF1 in Cancer

“…It is of great clinical interest to resolve the functions of HSF1 and HSPs in this process. HSF1 may decrease transcription and increase the degradation of ERa (181), while HSP70 and HSP90 can bind to steroid receptors and alter their activity (182). HER2, overexpressed in up to 50% of breast carcinoma cases, is known to promote tumor cell growth.…”