Modulating HSF1 levels impacts expression of the estrogen receptor ? 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 ? (ER?), 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 ER? degradation, decreased expression of ER?-activated genes, and antiestrogen resistance. Furthermore, we demonstrate that reducing HSF1 levels reinstates expression of the ER? 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 ER?-dependent transcriptional program leading to endocrine resistance in breast cancer.

SUBMITTER: Silveira MA 

PROVIDER: S-EPMC7893817 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature