Extending aromatase inhibitor sensitivity in hormone resistant breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Aromatase inhibitors (AIs) are standard for ER+ breast cancer but face acquired resistance.
• 25% of breast cancers are ERα-negative and innately resistant to AIs.
• Mechanisms of resistance involve reduced ERα and enhanced HER2 signaling or epigenetic silencing of ERα.

Purpose of the Study:

• To investigate novel therapeutic strategies to overcome acquired and innate resistance to AIs.
• To evaluate the efficacy of combining HER2 inhibition with AI therapy.
• To explore epigenetic modulation for restoring ERα expression in ERα-negative tumors.

Main Methods:

• Mouse models with acquired AI resistance were treated with trastuzumab (HER2 antibody) and letrozole.
• ERα-negative MDA-MB-231 cells were treated with entinostat (ENT) and letrozole.
• Tumor growth, ERα expression, HER2/p-MAPK signaling, and lung metastasis were assessed.

Main Results:

• Combined trastuzumab and letrozole restored ERα expression and significantly suppressed tumor growth in resistant models.
• Entinostat treatment increased ERα and aromatase expression in ERα-negative cells.
• ENT plus letrozole markedly reduced tumor growth and lung metastasis in ERα-negative models.

Conclusions:

• Dual inhibition of HER2 and ERα signaling is crucial for overcoming acquired AI resistance.
• Epigenetic therapy with ENT can re-sensitize ERα-negative breast cancer to AIs.
• These combination strategies offer potential for improved treatment outcomes in resistant breast cancer populations.