HER3 enhances ATF4 induction and survival in breast cancer cells during endoplasmic reticulum stress

Area of Science:

• Oncology
• Molecular Biology
• Cellular Stress Response

Background:

• Oncogenic signaling and stress response pathways are crucial in tumorigenesis and therapy resistance.
• The role of HER3, a HER/ErbB receptor family member, in these interactions, particularly during endoplasmic reticulum (ER) stress, remains largely unexplored.
• Aberrant HER3 expression is observed in various cancers, including breast cancer.

Purpose of the Study:

• To investigate the interaction between HER3 signaling and the integrated stress response (ISR) pathway during ER stress in breast cancer cells.
• To elucidate the role of HER3 in the induction of ATF4, a key transcription factor in the ISR and unfolded protein response (UPR).

Main Methods:

• Utilized HER2-overexpressing SKBR3 and non-overexpressing MCF7 breast cancer cell lines.
• Investigated the effect of ligand-activated HER3 and HER2/HER3 signaling inhibition (genetic knockdown and pharmacological) on ATF4 induction.
• Assessed cell death during ER stress following HER3 knockdown.
• Examined HER3 depletion effects on ATF4 induction during sustained ER stress.

Main Results:

• HER3 cooperates with HER2 to enhance ATF4 induction during ER stress.
• Ligand-activated HER3 enhances ATF4 induction, while HER2/HER3 signaling inhibition reduces it in both SKBR3 and MCF7 cells.
• HER3 knockdown in SKBR3 cells increased cell death under ER stress conditions.
• Depletion of HER3 during sustained ER stress led to attenuated ATF4 induction, suggesting ER stress-associated downregulation.

Conclusions:

• The HER3-ATF4 axis is a dynamically regulated mechanism that tunes the cellular stress response.
• This axis plays a significant role in managing ER stress and influences cell survival in breast cancer.
• Findings suggest potential therapeutic strategies targeting the HER3-ATF4 pathway for cancer treatment.