17β-Estradiol Activates HSF1 via MAPK Signaling in ERα-Positive Breast Cancer Cells

Abstract

Heat Shock Factor 1 (HSF1) is a key regulator of gene expression during acute environmental stress that enables the cell survival, which is also involved in different cancer-related processes. A high level of HSF1 in estrogen receptor (ER)-positive breast cancer patients correlated with a worse prognosis. Here we demonstrated that 17<i>β</i>-estradiol (E2), as well as xenoestrogen bisphenol A and ER<i>α</i> agonist propyl pyrazole triol, led to HSF1 phosphorylation on S326 in ER<i>α</i> positive but not in ER<i>α</i>-negative mammary breast cancer cells. Furthermore, we showed that MAPK signaling (via MEK1/2) but not mTOR signaling was involved in E2/ER<i>α</i>-dependent activation of HSF1. E2-activated HSF1 was transcriptionally potent and several genes essential for breast cancer cells growth and/or ER<i>α</i> action, including <i>HSPB8</i>, <i>LHX4</i>, <i>PRKCE</i>, <i>WWC1</i>, and <i>GREB1</i>, were activated by E2 in a HSF1-dependent manner. Our findings suggest a hypothetical positive feedback loop between E2/ER<i>α</i> and HSF1 signaling, which may support the growth of estrogen-dependent tumors.