Activation of PERK/eIF2α/ATF4 signaling inhibits ERα expression in breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cellular Stress Response

Background:

• Estrogen receptor alpha (ERα) drives 70-80% of breast cancers.
• Endoplasmic reticulum stress (ERS) and the unfolded protein response (UPR) are implicated in cancer development.
• The precise impact of ERS on ERα expression in ER-positive breast cancer (ER+ BC) requires further clarification.

Purpose of the Study:

• To investigate the regulatory mechanisms by which ERS influences ERα expression in ER+ BC.
• To elucidate the specific signaling pathways involved in ERS-mediated regulation of ERα.

Main Methods:

• Utilized ERS inducers thapsigargin (TG) and brefeldin A (BFA) in ER+ BC cell lines.
• Employed Chromatin Immunoprecipitation followed by quantitative PCR (ChIP-qPCR) and luciferase reporter gene assays.
• Assessed tumor cell growth in vitro and in vivo following PERK signaling activation or ATF4 overexpression.

Main Results:

• ERS significantly decreased ERα at both protein and mRNA levels in ER+ BC cells.
• The PERK/eIF2α/ATF4 signaling pathway mediates ERS-induced suppression of ERα.
• ERS induction enhanced ATF4 binding to the ESR1 promoter, reducing its activity and ERα expression.
• Selective PERK activation or ATF4 overexpression inhibited ERα expression and tumor cell growth.

Conclusions:

• ERS transcriptionally suppresses ERα expression through the PERK/eIF2α/ATF4 signaling pathway.
• This mechanism provides a novel understanding of ERα regulation in ER+ BC.
• Targeting the PERK pathway of the UPR presents a potential therapeutic strategy for ER+ BC.