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

Natalia Vydra,Wiesława Widłak,Bartłomiej Gielniewski,Agnieszka Toma-Jonik,Tomasz Stokowy,Joanna Korfanty,Patryk Janus,Katarzyna Mrowiec,Bartosz Wojtaś,Anna Długajczyk

doi:10.3390/cancers11101533

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 17β-estradiol (E2), as well as xenoestrogen bisphenol A and ERα agonist propyl pyrazole triol, led to HSF1 phosphorylation on S326 in ERα positive but not in ERα-negative mammary breast cancer cells. Furthermore, we showed that MAPK signaling (via MEK1/2) but not mTOR signaling was involved in E2/ERα-dependent activation of HSF1. E2activated HSF1 was transcriptionally potent and several genes essential for breast cancer cells growth and/or ERα action, including HSPB8, LHX4, PRKCE, WWC1, and GREB1, were activated by E2 in a HSF1-dependent manner. Our findings suggest a hypothetical positive feedback loop between E2/ERα and HSF1 signaling, which may support the growth of estrogen-dependent tumors.

Highlights

Heat Shock Factor 1 (HSF1) is an evolutionarily conserved transcription factor, which is activated under stress conditions
Looking for the cross-talk between estrogen and HSF1 signaling pathways we found that E2 can activate HSF1 in ERα-positive breast cancer cells through MEK1/2 signaling
This is a very important finding bearing in mind that up to 80% of all breast cancer cases rely on supplies of the estrogen to grow, while HSF1 is frequently overexpressed in breast cancer and its high level in estrogen receptor (ER)-positive cases negatively correlates with the survival time of patients [7,8]

Summary

Introduction

Heat Shock Factor 1 (HSF1) is an evolutionarily conserved transcription factor, which is activated under stress conditions Once activated, it regulates the expression of heat shock proteins (HSPs). HSF1 affects many aspects of cellular metabolism that are important for the cancer phenotype: it modulates signaling pathways associated with growth and proliferation, apoptosis, glucose metabolism, angiogenesis, and cell motility [3,4]. It modulates signaling pathways altered by the expression of mutant oncogenic proteins, affecting the phenotype of cancer cells [5].

Objectives

Methods

Findings

Conclusion